View source for T helper cell

{{Short description|Type of immune cell}}
{{redirect|Th2|the professional wrestling tag team|The Hybrid 2}}

[[File:Activation of T and B cells.png|thumb|right|400px|Activation of macrophage or B cell by T helper cell]]
The '''T helper cells''' ('''T<sub>h</sub> cells'''), also known as '''CD4<sup>+</sup> cells''' or '''CD4-positive cells''', are a type of [[T cell]] that play an important role in the [[adaptive immune system]]. They aid the activity of other immune cells by releasing [[cytokines]]. They are considered essential in [[B cell]] [[Immunoglobulin class switching|antibody class switching]], breaking [[Cross-presentation|cross-tolerance]] in dendritic cells, in the activation and growth of [[cytotoxic T cell]]s, and in maximizing [[bactericidal]] activity of [[phagocytes]] such as [[macrophages]] and [[neutrophil]]s. CD4<sup>+</sup> cells are mature T<sub>h</sub> cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4<sup>+</sup> cells determines susceptibility to a broad class of [[autoimmune disease]]s.<ref>{{cite journal | vauthors = Burren OS, Rubio García A, Javierre BM, Rainbow DB, Cairns J, Cooper NJ, Lambourne JJ, Schofield E, Castro Dopico X, Ferreira RC, Coulson R, Burden F, Rowlston SP, Downes K, Wingett SW, Frontini M, Ouwehand WH, Fraser P, Spivakov M, Todd JA, Wicker LS, Cutler AJ, Wallace C | display-authors = 6 | title = Chromosome contacts in activated T cells identify autoimmune disease candidate genes | journal = Genome Biology | volume = 18 | issue = 1 | article-number = 165 | date = September 2017 | pmid = 28870212 | pmc = 5584004 | doi = 10.1186/s13059-017-1285-0 | doi-access = free }}</ref>

== Structure and function ==

T<sub>h</sub> cells contain and release cytokines to aid other immune cells. Cytokines are small protein mediators that alter the behavior of target cells that express [[Receptor (biochemistry)|receptors]] for those cytokines. These cells help polarize the immune response depending on the nature of the immunological insult (for example; virus vs. extracellular [[Bacteria|bacterium]] vs. intracellular bacterium vs. [[Parasitic worm|helminth]] vs. fungus vs. protist).{{cn|date=February 2024}}

Mature T<sub>h</sub> cells express the surface protein [[CD4]] and are referred to as '''CD4<sup>+</sup> T cells'''. CD4<sup>+</sup> T cells are generally treated as having a pre-defined role as helper T cells within the [[immune system]]. For example, when an [[antigen-presenting cell]] displays a [[peptide]] antigen on [[MHC class II]] proteins, a CD4<sup>+</sup> cell will aid those cells through a combination of cell to cell interactions (e.g. [[CD40 (protein)]] and [[CD154|CD40L]]) and through [[cytokines]].{{cn|date=April 2025}}

T<sub>h</sub> cells are not a monolithic immunological entity because they are diverse in terms of function and their interaction with partner cells. In general, mature naive T cells are stimulated by professional antigen presenting cells to acquire an effector function. These are defined by the presence of a lineage-determining (or lineage-specifying) transcription factor (also called [[master regulator]], though the term has been criticized for being too reductive).<ref>{{cite journal | vauthors = Oestreich KJ, Weinmann AS | title = Master regulators or lineage-specifying? Changing views on CD4+ T cell transcription factors | journal = Nature Reviews. Immunology | volume = 12 | issue = 11 | pages = 799–804 | date = November 2012 | pmid = 23059426 | pmc = 3584691 | doi = 10.1038/nri3321 }}</ref> The loss of function in a lineage specifying transcription factor results in the absence of the corresponding class of helper T cell which can be devastating for the health of the host.{{cn|date=April 2025}}

== Activation of naive helper T cells ==
[[File:T-dependent B cell activation.png|thumb|right|400px|T-cell dependent B-cell activation, showing TH2-cell (left) B-cell (right) and several interaction molecules self-made according to Janeway et al, ''Immunologie'' (Berlin, 2002)]]

Following [[T cell#Development|development]] in the [[thymus]], these cells (termed recent thymic emigrants (RTE)) egress from the thymus and home to [[secondary lymphoid organs]] (SLO; [[spleen]] and [[lymph nodes]]). Of note, only a very small minority of T cells egresses from the thymus (estimates commonly range from 1–5% but some experts feel even this is generous).<ref>{{cite journal | vauthors = Fink PJ | title = The biology of recent thymic emigrants | journal = Annual Review of Immunology | volume = 31 | issue = 1 | pages = 31–50 | date = 2013-03-21 | pmid = 23121398 | doi = 10.1146/annurev-immunol-032712-100010 }}</ref> Maturation of RTE in SLO results in the generation of mature [[naive T cell]]s (naïve meaning they have never been exposed to the [[antigen]] that they are programmed to respond to), but naive T cells now lack or have [[Downregulation and upregulation|downregulated]] (reduced) expression of the RTE-related surface markers, such as [[CD31]], [[PTK7]], Complement Receptor 1 and 2 ([[Complement receptor 1|CR1]], [[Complement receptor 2|CR2]]) and the production of [[Interleukin 8|interleukin 8 (IL-8)]].<ref>{{cite journal | vauthors = van den Broek T, Borghans JA, van Wijk F | title = The full spectrum of human naive T cells | journal = Nature Reviews. Immunology | volume = 18 | issue = 6 | pages = 363–373 | date = June 2018 | pmid = 29520044 | doi = 10.1038/s41577-018-0001-y | s2cid = 3736563 }}</ref><ref>{{cite journal | vauthors = van den Broek T, Delemarre EM, Janssen WJ, Nievelstein RA, Broen JC, Tesselaar K, Borghans JA, Nieuwenhuis EE, Prakken BJ, Mokry M, Jansen NJ, van Wijk F | display-authors = 6 | title = Neonatal thymectomy reveals differentiation and plasticity within human naive T cells | journal = The Journal of Clinical Investigation | volume = 126 | issue = 3 | pages = 1126–1136 | date = March 2016 | pmid = 26901814 | pmc = 4767338 | doi = 10.1172/JCI84997 }}</ref> Like all T cells, they express the [[T cell receptor]]-[[CD3 receptor|CD3]] complex. The T cell receptor (TCR) consists of both constant and variable regions. The variable region determines what antigen the T cell can respond to. CD4<sup>+</sup> T cells have TCRs with an affinity for [[Class II MHC]], and CD4 is involved in determining MHC affinity during maturation in the [[thymus]]. Class II MHC proteins are generally only found on the surface of professional [[antigen-presenting cell]]s (APCs). Professional antigen-presenting cells are primarily [[dendritic cells]], [[macrophages]] and [[B cells]], although dendritic cells are the only cell group that expresses MHC Class II [[Gene expression|constitutively]] (at all times). Some APCs also bind native (or unprocessed) antigens to their surface, such as [[follicular dendritic cells]] (these are ''not'' the same type of cells as the [[dendritic cell]]s of the immune system but rather have a non-hematopoietic origin, and in general lack MHC Class II, meaning they are not true professional antigen-presenting cells; however, follicular dendritic cells may acquire MHC Class II proteins via exosomes that become attached to them<ref>{{cite journal | vauthors = Roche PA, Furuta K | title = The ins and outs of MHC class II-mediated antigen processing and presentation | journal = Nature Reviews. Immunology | volume = 15 | issue = 4 | pages = 203–216 | date = April 2015 | pmid = 25720354 | pmc = 6314495 | doi = 10.1038/nri3818 }}</ref>). T cells require [[Antigen presentation|antigens to be processed]] into short fragments which form [[linear epitope]]s on MHC Class II (in the case of helper T cells because they express CD4) or MHC class I (in the case of [[cytotoxic T cell]]s which express [[CD8]]). MHC Class II binding pockets are flexible with respect to the length of the peptides they hold. Generally, there are 9 core amino acid residues with several flanking amino acids which form a length of about 12–16 amino acids total<ref>{{cite journal | vauthors = Unanue ER, Turk V, Neefjes J | title = Variations in MHC Class II Antigen Processing and Presentation in Health and Disease | journal = Annual Review of Immunology | volume = 34 | issue = 1 | pages = 265–297 | date = May 2016 | pmid = 26907214 | doi = 10.1146/annurev-immunol-041015-055420 }}</ref> but have been known to hold as many as 25 amino acids.<ref>{{cite journal | vauthors = Wieczorek M, Abualrous ET, Sticht J, Álvaro-Benito M, Stolzenberg S, Noé F, Freund C | title = Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation | journal = Frontiers in Immunology | volume = 8 | page = 292 | date = 2017-03-17 | pmid = 28367149 | pmc = 5355494 | doi = 10.3389/fimmu.2017.00292 | doi-access = free }}</ref> By comparison, MHC Class I proteins are usually 9-10 peptides long.<ref>{{cite journal | vauthors = Trolle T, McMurtrey CP, Sidney J, Bardet W, Osborn SC, Kaever T, Sette A, Hildebrand WH, Nielsen M, Peters B | display-authors = 6 | title = The Length Distribution of Class I-Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele-Specific Binding Preference | journal = Journal of Immunology | volume = 196 | issue = 4 | pages = 1480–1487 | date = February 2016 | pmid = 26783342 | pmc = 4744552 | doi = 10.4049/jimmunol.1501721 }}</ref> The activation of naive T cells is commonly explained in terms of the 3-signal model, elaborated upon below.<ref>{{Cite book| vauthors = Murphy K  |title=Janeway's immunobiology|date=2017|publisher=Garland Science|isbn=978-0-8153-4551-0|oclc=1020120603}}</ref>

=== Activation (signal 1) ===

[[File:Antigen presentation.svg|thumb|300px|Antigen presentation stimulates naïve CD8+ and CD4+ T cells to become mature [[Cytotoxic T cell|"cytotoxic" CD8+ cells]] and "helper" CD4+ cells respectively .]]During an immune response, [[Antigen-presenting cell#Professional APCs|professional antigen-presenting cells]] (APCs) [[Endocytosis|endocytose]] antigens (typically bacteria or viruses), which undergo [[antigen processing|processing]], then travel from the infection site to the [[lymph node]]s. Typically, the APC responsible is a dendritic cell. If the antigen expresses appropriate molecular patterns (sometimes known as signal 0), it can induce maturation of the dendritic cell which results in enhanced expression of costimulatory molecules needed to activate T cells (see signal 2)<ref>{{cite journal | vauthors = Guy B | title = The perfect mix: recent progress in adjuvant research | journal = Nature Reviews. Microbiology | volume = 5 | issue = 7 | pages = 505–517 | date = July 2007 | pmid = 17558426 | doi = 10.1038/nrmicro1681 | s2cid = 25647540 }}</ref> and MHC Class II.<ref>{{cite journal | vauthors = Hammer GE, Ma A | title = Molecular control of steady-state dendritic cell maturation and immune homeostasis | journal = Annual Review of Immunology | volume = 31 | issue = 1 | pages = 743–791 | date = 2013-03-21 | pmid = 23330953 | pmc = 4091962 | doi = 10.1146/annurev-immunol-020711-074929 }}</ref> Once at the lymph nodes, the APCs begin to present antigen peptides that are bound to Class II MHC, allowing CD4<sup>+</sup> T cells that express the specific TCRs against the peptide/MHC complex to activate.{{cn|date=June 2022}}

When a T<sub>h</sub> cell encounters and recognizes the antigen on an APC, the [[T cell receptor|TCR]]-[[CD3 (immunology)|CD3]] complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. [[CD4]], a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. It is estimated that approximately 50 of these interactions are required for the activation of a helper T cell and assemblies known as microclusters have been observed forming between the TCR-CD3-CD4 complexes of the T cell and the MHC Class II proteins of the dendritic cell at the zone of contact. When these all come together, the CD4 is able to recruit a kinase called [[Lck]] which phosphorylates [[immunoreceptor tyrosine-based activation motif]]s (ITAMs) present on the CD3 gamma, delta, epsilon, and zeta chains. The protein [[ZAP70|ZAP-70]] can bind these phosphorylated ITAMs via its [[SH2 domain]] and then itself becomes phosphorylated, wherein it orchestrates the downstream signaling required for T cell activation. Lck activation is controlled by the opposing actions of [[PTPRC|CD45]] and [[Tyrosine-protein kinase CSK|Csk]].<ref>{{cite journal | vauthors = Zamoyska R | title = Why is there so much CD45 on T cells? | journal = Immunity | volume = 27 | issue = 3 | pages = 421–423 | date = September 2007 | pmid = 17892852 | doi = 10.1016/j.immuni.2007.08.009 | doi-access = free }}</ref> CD45 activates Lck by dephosphorylating a tyrosine in its C-terminal tail, while Csk phosphorylates Lck at that site. The loss of CD45 produces a form of SCID because failure to activate Lck prevents appropriate T cell signaling. Memory T cells also make use of this pathway and have higher levels of Lck expressed and the function of Csk is inhibited in these cells.<ref name="pmid31641081">{{cite journal | vauthors = Courtney AH, Shvets AA, Lu W, Griffante G, Mollenauer M, Horkova V, Lo WL, Yu S, Stepanek O, Chakraborty AK, Weiss A | display-authors = 6 | title = CD45 functions as a signaling gatekeeper in T cells | journal = Science Signaling | volume = 12 | issue = 604 | article-number = eaaw8151 | date = October 2019 | pmid = 31641081 | pmc = 6948007 | doi = 10.1126/scisignal.aaw8151 }}</ref>

The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the T<sub>h</sub> cell adhere during T<sub>h</sub> cell activation, but the integrin protein [[LFA-1]] on the T cell and [[Intercellular adhesion molecule|ICAM]] on the APC are the primary molecules of adhesion in this cell interaction.{{citation needed|date=August 2020}}

It is unknown what role the relatively bulky extracellular region of CD45 plays during cell interactions, but CD45 has various isoforms that change in size depending on the T<sub>h</sub> cell's activation and maturation status. For example, CD45 shortens in length following T<sub>h</sub> activation (CD45RA<sup>+</sup> to CD45RO<sup>+</sup>), but whether this change in length influences activation is unknown. It has been proposed that the larger CD45RA may decrease the accessibility of the T cell receptor for the antigen-MHC molecule, thereby necessitating an increase in the affinity (and specificity) of the T cell for activation. However, once the activation has occurred, CD45 shortens, allowing easier interactions and activation as an effector T helper cell.{{Citation needed|date=July 2007}}

===Survival (signal 2)===
Having received the first TCR/CD3 signal, the naïve T cell must activate a second independent biochemical pathway, known as Signal 2. This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen. If this second signal is not present during initial antigen exposure, the T cell presumes that it is auto-reactive. This results in the cell becoming [[anergy|anergic]] (anergy is generated from the unprotected biochemical changes of Signal 1). Anergic cells will not respond to any antigen in the future, even if both signals are present later on. These cells are generally believed to circulate throughout the body with no value until they undergo [[apoptosis]].<ref>{{cite journal | vauthors = Elmore S | title = Apoptosis: a review of programmed cell death | journal = Toxicologic Pathology | volume = 35 | issue = 4 | pages = 495–516 | date = June 2007 | pmid = 17562483 | pmc = 2117903 | doi = 10.1080/01926230701320337 }}</ref>

The second signal involves an interaction between [[CD28]] on the CD4<sup>+</sup> T cell and the proteins [[CD80]] (B7.1) or [[CD86]] (B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are also known as [[Co-stimulation|co-stimulatory molecules]].{{citation needed|date=August 2020}}

Although the verification stage is necessary for the activation of naïve helper T cells, the importance of this stage is best demonstrated during the similar activation mechanism of CD8<sup>+</sup> [[cytotoxic T cell]]s. As naïve CD8<sup>+</sup> T cells have no true bias towards foreign sources, these T cells must rely on the activation of CD28 for confirmation that they recognize a foreign antigen (as CD80/CD86 is only expressed by active APC's). CD28 plays an important role in decreasing the risk of T cell auto-immunity against host antigens.{{citation needed|date=August 2020}}

Once the naïve T cell has both pathways activated, the biochemical changes induced by Signal 1 are altered, allowing the cell to activate instead of undergoing anergy. The second signal is then obsolete; only the first signal is necessary for future activation. This is also true for memory T cells, which is one example of [[Adaptive immune system|learned immunity]]. Faster responses occur upon reinfection because memory T cells have already undergone confirmation and can produce effector cells much sooner.{{citation needed|date=August 2020}}

=== Differentiation (signal 3) ===
Once the two-signal activation is complete the T helper cell (T<sub>h</sub>) then allows itself to [[Cell growth|proliferate]]. It achieves this by releasing a potent T cell growth factor called [[interleukin 2]] (IL-2) which acts upon itself in an [[autocrine]] fashion.<ref name="Morgan, Ruscetti, & Gallo 1976">{{Cite journal |vauthors = Morgan DA, Ruscetti FW, Gallo R |title = Selective in vitro growth of T lymphocytes from normal human bone marrows |journal = Science |volume = 193 |issue = 4253 |pages = 1007–1008 |year = 1976 |pmid = 181845 |doi = 10.1126/science.181845 }}</ref> Activated T cells also produce the alpha sub-unit of the [[IL-2 receptor]] ([[CD25]] or IL-2R), enabling a fully functional receptor that can bind with IL-2, which in turn activates the T cell's proliferation pathways.{{citation needed|date=August 2020}}

The [[autocrine]] or [[paracrine]] secretion of IL-2 can bind to that same T<sub>h</sub> cell or neighboring T<sub>h</sub>'s via the IL-2R thus driving proliferation and clonal expansion. The T<sub>h</sub> cells receiving both signals of activation and proliferation will then become T<sub>h</sub>0 (T helper 0) cells that secrete IL-2, [[interleukin 4|IL-4]] and [[interferon gamma]] (IFN-γ). The T<sub>h</sub>0 cells will then differentiate into T<sub>h</sub>1 or T<sub>h</sub>2 cells depending on [[cytokine]] environment. IFN-γ drives T<sub>h</sub>1 cell production while [[interleukin 10|IL-10]] and IL-4 inhibit T<sub>h</sub>1 cell production. Conversely, IL-4 drives T<sub>h</sub>2 cell production and IFN-γ inhibits T<sub>h</sub>2 cells. These cytokines are [[pleiotropic]] and carry out many other functions of the immune response.{{citation needed|date=August 2020}}

== Effector function ==

In 1991, three groups reported discovering CD154, which is the molecular basis of T cell helper function. [[Seth Lederman]] at [[Columbia College of Physicians and Surgeons|Columbia University]] generated a murine monoclonal antibody, 5c8 that inhibited contact-dependent T cell helper function in human cells which characterized the 32 kDa surface protein transiently expressed on CD4<sup>+</sup> T cells.<ref name="ReferenceA">{{cite journal | vauthors = Lederman S, Yellin MJ, Krichevsky A, Belko J, Lee JJ, Chess L | title = Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help) | journal = The Journal of Experimental Medicine | volume = 175 | issue = 4 | pages = 1091–1101 | date = April 1992 | pmid = 1348081 | pmc = 2119166 | doi = 10.1084/jem.175.4.1091 }}</ref>  Richard Armitage at [[Amgen|Immunex]] cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig.<ref>{{cite journal | vauthors = Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, Anderson DM, Gimpel SD, Davis-Smith T, Maliszewski CR | display-authors = 6 | title = Molecular and biological characterization of a murine ligand for CD40 | journal = Nature | volume = 357 | issue = 6373 | pages = 80–82 | date = May 1992 | pmid = 1374165 | doi = 10.1038/357080a0 | s2cid = 4336943 | bibcode = 1992Natur.357...80A }}</ref>  Randolph Noelle at [[Geisel School of Medicine|Dartmouth Medical School]] generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.<ref>{{cite journal | vauthors = Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A | title = A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 14 | pages = 6550–6554 | date = July 1992 | pmid = 1378631 | pmc = 49539 | doi = 10.1073/pnas.89.14.6550 | doi-access = free | bibcode = 1992PNAS...89.6550N }}</ref>

== Determination of the effector T cell response ==
Helper T cells are capable of influencing a variety of immune cells, and the T cell response generated (including the [[extracellular]] signals such as [[cytokine]]s) can be essential for a successful outcome from infection. In order to be effective, helper T cells must determine which cytokines will allow the immune system to be most useful or beneficial for the host. Understanding exactly how helper T cells respond to immune challenges is currently of major interest in [[immunology]], because such knowledge may be very useful in the treatment of disease and in increasing the effectiveness of [[vaccination]].{{citation needed|date=August 2020}}

=== T<sub>h</sub>1/T<sub>h</sub>2 model ===
Proliferating naive CD4<sup>+</sup> cells differentiate into a number of effector T-cell subtypes. Historically, the first division of CD4<sup>+</sup> cells recognized by researchers were T helper cell types 1 and 2, or Th<sub>1</sub> and Th<sub>2</sub>.<ref name="Mossmann et al 1986">{{cite journal |vauthors=Mosmann TR, Cherwinski HJ, Bond MW, Giedlin MA, Coffman RL |title=Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins |journal=Journal of Immunology |volume=136 |issue=7 |pages=2348–2357 |date=April 1986 |doi=10.4049/jimmunol.136.7.2348}}</ref> This has come to be referred to as the T<sub>h</sub>1/T<sub>h</sub>2 model.<ref name="van Oosterhout & Motta 2005">{{cite journal |vauthors=Stelma F, Lutter R, van Wetering S, van den Worm E, Hiemstra PS, van den Bosch JM, van der Zee JS |title=Regulation of CD4+ T cell responses in the airways of allergic asthmatics after allergen challenge |journal=European Respiratory Journal |volume=26 |issue=2 |pages=246–252 |date=August 2005 |doi=10.1183/09031936.05.00014105 |pmid=15802329 }}</ref> There are now a variety of recognized CD4<sup>+</sup> subtypes such as [[Th_9_cell|Th<sub>9</sub>]], [[T_helper_17_cell|Th<sub>17</sub>]], [[Regulatory_T_cell|T<sub>reg</sub>]] and [[Follicular_B_helper_T_cells|T<sub>fh</sub>]].<ref>{{cite journal |vauthors=Luckheeram RV, Zhou R, Verma AD, Xia B |title=CD4+T cells: differentiation and functions |journal=Clinical and Developmental Immunology |date=2012 |volume=2012 |article-number=925135 |doi=10.1155/2012/925135 |doi-access=free |pmid=22701411 |pmc=3368297}}</ref>  

T<sub>h</sub>1 helper cells lead to an increased [[Cell-mediated immunity|cell-mediated response]] (primarily by [[macrophage]]s and [[cytotoxic T cell]]s),<ref name="pmid27313405">{{cite journal | vauthors = Belizário JE, Brandão W, Rossato C, Peron JP | title = Thymic and Postthymic Regulation of Naïve CD4(+) T-Cell Lineage Fates in Humans and Mice Models | journal = Mediators of Inflammation | volume = 2016 | article-number = 9523628 | date = 2016 | pmid = 27313405 | pmc = 4904118 | doi = 10.1155/2016/9523628 | doi-access = free }}</ref>  typically against intracellular bacteria and protozoa. They are triggered by the polarising cytokine IL-12 and their effector cytokines are IFN-γ and IL-2. The main effector cells of T<sub>h</sub>1 immunity are macrophages as well as CD8 T cells, IgG B cells, and IFN-γ CD4 T cells. The key T<sub>h</sub>1 transcription factors are STAT4 and T-bet. IFN-γ secreted by CD4 T cells can activate macrophages to phagocytose and digest intracellular bacteria and protozoa. In addition, IFN-γ can activate [[Nitric oxide synthase#iNOS|iNOS]] (inducible nitric oxide synthase) to produce nitric oxide free radicals to directly kill intracellular bacteria and protozoa. T<sub>h</sub>1 overactivation against autoantigens will cause  [[Type IV hypersensitivity|Type IV]] or delayed-type hypersensitivity reaction.  [[Mantoux test|Tuberculin reaction]] and Type 1 diabetes belong to this category of autoimmunity.<ref name=Zhu2008>{{cite journal | vauthors = Zhu J, Paul WE | title = CD4 T cells: fates, functions, and faults | journal = Blood | volume = 112 | issue = 5 | pages = 1557–1569 | date = September 2008 | pmid = 18725574 | pmc = 2518872 | doi = 10.1182/blood-2008-05-078154 }}</ref>

T<sub>h</sub>2 helper cells lead to a [[Humoral immunity|humoral immune response]],<ref name="pmid27313405" /> typically against extracellular parasites such as [[helminths]]. They are triggered by the polarising cytokines IL-4 and IL-2, and their effector cytokines are IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25. The main effector cells are eosinophils, basophils, and mast cells as well as B cells, and IL-4/IL-5 CD4 T cells. The key T<sub>h</sub>2 transcription factors are [[STAT6]] and [[GATA3]].<ref>{{cite journal | vauthors = Wan YY | title = GATA3: a master of many trades in immune regulation | journal = Trends in Immunology | volume = 35 | issue = 6 | pages = 233–242 | date = June 2014 | pmid = 24786134 | pmc = 4045638 | doi = 10.1016/j.it.2014.04.002 }}</ref> IL-4 is the positive feedback cytokine for T<sub>h</sub>2 cells differentiation. Besides, IL-4 stimulates B-cells to produce IgE antibodies, which in turn stimulate mast cells to release [[histamine]], [[serotonin]], and leukotriene to cause broncho-constriction, intestinal peristalsis, gastric fluid acidification to expel helminths. IL-5 from CD4 T cells will activate eosinophils to attack helminths. IL-10 suppresses T<sub>h</sub>1 cells differentiation and function of dendritic cells.  T<sub>h</sub>2 overactivation against antigen will cause [[Type I hypersensitivity]] which is an allergic reaction mediated by IgE. Allergic rhinitis, atopic dermatitis, and asthma belong to this category of overactivation .<ref name=Zhu2008/>  In addition to expressing different cytokines, T<sub>h</sub>2 cells also differ from T<sub>h</sub>1 cells in their cell surface glycans (oligosaccharides), which makes them less susceptible to some inducers of cell death.<ref>{{cite journal | vauthors = Maverakis E, Kim K, Shimoda M, Gershwin ME, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB | display-authors = 6 | title = Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review | journal = Journal of Autoimmunity | volume = 57 | issue = 6 | pages = 1–13 | date = February 2015 | pmid = 25578468 | pmc = 4340844 | doi = 10.1016/j.jaut.2014.12.002 }}</ref><ref>{{cite journal | vauthors = Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirier F, Riley EM, Baum LG, Rabinovich GA | display-authors = 6 | title = Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death | journal = Nature Immunology | volume = 8 | issue = 8 | pages = 825–834 | date = August 2007 | pmid = 17589510 | doi = 10.1038/ni1482 | s2cid = 41286571 }}</ref>

[[Image:Lymphocyte activation.png|thumb|407x407px|center|T<sub>h</sub>1/T<sub>h</sub>2 Model for helper T cells. An antigen is ingested and processed by an [[antigen-presenting cell|APC]]. It presents fragments from it to T cells. The upper, T<sub>h</sub>0, is a T helper cell. The fragment is presented to it by [[major histocompatibility complex 2|MHC2]].<ref name=Rang223>{{cite book | vauthors = Rang HP, Dale MM, Riter JM, Moore PK |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 }} Page 223</ref> IFN-γ, [[interferon γ]]; TGF-β, [[transforming growth factor β]]; mø, [[macrophage]]; IL-2, [[interleukin 2]]; IL-4, [[interleukin 4]]]]

{| class="wikitable"
|+ Th1/Th2 dichotomy
|-
!  !! Type 1/ T<sub>h</sub>1 !! Type 2/ T<sub>h</sub>2<ref name=Zhu2008/>
 |-
 | Main partner cell type || [[Macrophage]], [[Cytotoxic T cell|CD8<sup>+</sup> T cell]] || [[B-cell]], [[eosinophil]], [[mast cell]]
 |-
 | Cytokines produced  || [[Interferon gamma]] (IFNγ) and [[TNF-β]]. [[Interleukin 2]] and [[interleukin 10]] production has been reported in activated T<sub>h</sub>1 cell.<ref>{{cite journal | vauthors = Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O'Garra A | title = Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose | journal = Immunity | volume = 31 | issue = 2 | pages = 209–219 | date = August 2009 | pmid = 19646904 | pmc = 2791889 | doi = 10.1016/j.immuni.2009.05.012 }}</ref>
 | [[Interleukin 4]], [[interleukin 5]], [[interleukin 6]], [[interleukin 9]], [[interleukin 10]], [[interleukin 13]]
 |-
 | Immune stimulation promoted || [[Cell-mediated immunity|Cellular immune system]]. Maximizes the killing efficacy of the [[macrophages]] and the proliferation of cytotoxic [[CD8]]<sup>+</sup> T cells. Also promotes the production of IgG, an opsonizing antibody.
 | [[Humoral immune system]]. Stimulates [[B-cells]] into proliferation, to induce B-cell [[antibody class switching]], and to increase neutralizing [[antibody]] production (IgG, IgM and IgA as well as IgE antibodies).
 |-
 | Other functions || The Type 1 cytokine [[Interferon gamma|IFNγ]] increases the production of [[interleukin 12]] by dendritic cells and macrophages, and via positive feedback, IL-12 stimulates the production of [[interferon gamma|IFNγ]] in helper T cells, thereby promoting the T<sub>h</sub>1 profile. IFNγ also inhibits the production of cytokines such as [[interleukin 4]], an important cytokine associated with the Type 2 response, and thus it also acts to preserve its own response.
 | The Type 2 response promotes its own profile using two different cytokines. [[Interleukin 4]] acts on helper T cells to promote the production of T<sub>h</sub>2 cytokines (including itself; it is auto-regulatory), while [[interleukin 10]] (IL-10) inhibits a variety of cytokines including [[interleukin 2]] and [[interferon gamma|IFNγ]] in helper T cells and IL-12 in dendritic cells and macrophages. The combined action of these two cytokines suggests that once the T cell has decided to produce these cytokines, that decision is preserved (and also encourages other T cells to do the same).
|}

While we know about the types of cytokine patterns helper T cells tend to produce, we understand less about how the patterns themselves are decided. Various evidence suggests that the type of APC presenting the antigen to the T cell has a major influence on its profile. Other evidence suggests that the concentration of antigen presented to the T cell during primary activation influences its choice. The presence of some cytokines (such as the ones mentioned above) will also influence the response that will eventually be generated, but our understanding is nowhere near complete.

===T<sub>h</sub>17 helper cells===
{{Main|T helper 17 cell}}
[[T helper 17 cell|T<sub>h</sub>17 helper cells]] are a subset of T helper cells developmentally distinct from T<sub>h</sub>1 and T<sub>h</sub>2 lineages.
T<sub>h</sub>17 cells produce [[interleukin 17]] (IL-17), a pro-inflammatory substance, as well as [[interleukin 21|interleukins 21]] and [[interleukin 22|22]].<ref name=guglanikhader2010>{{cite journal|vauthors=Guglani L, Khader SA|title=Th17 cytokines in mucosal immunity and inflammation|journal=Current Opinion in HIV and AIDS|volume=5|issue=2|pages=120–127|year=2010|doi=10.1097/COH.0b013e328335c2f6|pmid=20543588|pmc=2892849}}</ref> This means that T<sub>h</sub>17 cells are especially good at fighting extracellular pathogens<ref name=guglanikhader2010/> and fungi, particularly during mucocutaneous immunity against ''[[Candida (fungus)|Candida]]'' spp.<ref>{{cite journal|vauthors=Tangye SG, Puel A|title=The Th17/IL-17 Axis and Host Defense Against Fungal Infections|year=2023|journal=Journal of Allergy and Clinical Immunology: In Practice|volume=11|issue=6|pages=1624–1634|doi=10.1016/j.jaip.2023.04.015|pmid=37116791|s2cid=258380150 }}</ref>

===THαβ helper cells===
THαβ helper cells provide the host immunity against viruses. Their differentiation is triggered by IFN α/β or [[Interleukin 10|IL-10]]. Their key effector cytokine is IL-10. Their main effector cells are [[natural killer cell|NK cells]] as well as CD8 T cells, IgG B cells, and IL-10 CD4 T cells. The key THαβ transcription factors are [[STAT1]] and STAT3 as well as IRFs. IL-10 from CD4 T cells activate NK cells' [[antibody-dependent cell-mediated cytotoxicity|ADCC]] to apoptose virus-infected cells and to induce host as well as viral DNA fragmentation. IFN alpha/beta can suppress transcription to avoid virus replication and transmission. Overactivation of THαβ against autoantigen will cause type 2 antibody-dependent cytotoxic hypersensitivity. [[Myasthenia gravis]] or [[Graves' disease]] belong to this category.<ref name="Wanchung Hu2007">{{cite thesis |degree=Ph.D. | vauthors = Hu W |title=Microarray analysis of PBMC gene expression profiles after Plasmodium falciparum malarial infection |publisher=Johns Hopkins University |year=2007}}</ref>

=== Limitations to the T<sub>h</sub>1/T<sub>h</sub>2 model ===
The interactions between cytokines from the T<sub>h</sub>1/T<sub>h</sub>2 model can be more complicated in some animals. For example, the T<sub>h</sub>2 cytokine [[Interleukin 10|IL-10]] inhibits cytokine production of both T<sub>h</sub> subsets in humans. Human IL-10 (hIL-10) suppresses the proliferation and cytokine production of all T cells and the activity of macrophages, but continues to stimulate [[plasma cells]], ensuring that antibody production still occurs. As such, hIL-10 is not believed to truly promote the T<sub>h</sub>2 response in humans, but acts to prevent over-stimulation of helper T cells while still maximising the production of [[antibody|antibodies]].There are also other types of T cells that can influence the expression and activation of helper T cells, such as natural [[regulatory T cells]], along with less common cytokine profiles such as the [[T helper 3 cell|T<sub>h</sub>3]] subset of helper T cells. Terms such as "regulatory" and "suppression" have become ambiguous after the discovery that helper CD4<sup>+</sup> T cells are also capable of regulating (and suppressing) their own responses outside of dedicated regulatory T cells.{{citation needed|date=August 2020}}

One major difference between regulatory T cells and effector T cells is that regulatory T cells typically serve to modulate and deactivate the immune response, while effector T cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their life cycle. The latter is a feature of T<sub>h</sub>3 cells, which transform into a regulatory subset after its initial activation and cytokine production.{{citation needed|date=August 2020}}

Both [[regulatory T cells]] and [[T helper 3 cell|T<sub>h</sub>3 cells]] produce the cytokine [[TGF β|transforming growth factor-beta]] (TGF-β) and IL-10. Both cytokines are inhibitory to helper T cells; TGF-β suppresses the activity of most of the immune system. There is evidence to suggest that TGF-β may not suppress activated Th2 cells as effectively as it might suppress naive cells, but it is not typically considered a Th2 cytokine.{{citation needed|date=August 2020}}

The novel characterisation of another T helper subtype, [[T helper 17 cell]]s (T<sub>h</sub>17)<ref name="Harrington2005">{{cite journal | vauthors = Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT | title = Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages | journal = Nature Immunology | volume = 6 | issue = 11 | pages = 1123–1132 | date = November 2005 | pmid = 16200070 | doi = 10.1038/ni1254 | s2cid = 11717696 }}</ref> has cast further doubt on the basic T<sub>h</sub>1/T<sub>h</sub>2 model. These [[interleukin 17|IL-17]] producing cells were initially described as a pathogenic population implicated in autoimmunity but are now thought to have their own distinct effector and regulatory functions. Of note, some evidence suggest that functional plasticity is an intrinsic capacity of T helper cells. Indeed, a study in mice demonstrated that T<sub>h</sub>17 cells transform into T<sub>h</sub>1 cells ''in vivo''.<ref>{{cite journal | vauthors = Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B | display-authors = 6 | title = Fate mapping of IL-17-producing T cells in inflammatory responses | journal = Nature Immunology | volume = 12 | issue = 3 | pages = 255–263 | date = March 2011 | pmid = 21278737 | pmc = 3040235 | doi = 10.1038/ni.1993 }}</ref> A subsequent study furthermore showed that extensive T helper cell plasticity is also prominent in humans.<ref>{{cite journal | vauthors = Larsen M, Arnaud L, Hié M, Parizot C, Dorgham K, Shoukry M, Kemula M, Barete S, Derai D, Sauce D, Amoura Z, Pène J, Yssel H, Gorochov G | display-authors = 6 | title = Multiparameter grouping delineates heterogeneous populations of human IL-17 and/or IL-22 T-cell producers that share antigen specificities with other T-cell subsets | journal = European Journal of Immunology | volume = 41 | issue = 9 | pages = 2596–2605 | date = September 2011 | pmid = 21688259 | doi = 10.1002/eji.201041131 | publisher = [[UPMC Paris 06]] Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-S 945 | s2cid = 24092508 | doi-access = free }}</ref>

Many of the cytokines in this article are also expressed by other immune cells (see individual cytokines for details), and it is becoming clear that while the original T<sub>h</sub>1/T<sub>h</sub>2 model is enlightening and gives insight into the functions of helper T cells, it is far too simple to define its entire role or actions. Some immunologists question the model completely, as some ''in vivo'' studies suggest that individual helper T cells usually do not match the specific cytokine profiles of the T<sub>h</sub> model, and many cells express cytokines from both profiles.<ref>{{cite journal | vauthors = Nakayamada S, Takahashi H, Kanno Y, O'Shea JJ | title = Helper T cell diversity and plasticity | journal = Current Opinion in Immunology | volume = 24 | issue = 3 | pages = 297–302 | date = June 2012 | pmid = 22341735 | pmc = 3383341 | doi = 10.1016/j.coi.2012.01.014 }}</ref> That said, the T<sub>h</sub> model has still played an important part in developing our understanding of the roles and behaviour of helper T cells and the cytokines they produce during an immune response.{{cn|date=April 2025}}

Studies by Stockinger et al. revealed that another T helper subset may exist. [[Th 9 cells|Th9 cells]] are claimed to be an IL9 ([[interleukin 9]])–producing T cell subset focused on defending [[helminth]] infections.<ref name="pmid19008928">{{cite journal | vauthors = Tato CM, Cua DJ | title = Alternative lifestyles of T cells | journal = Nat Immunol | volume = 9 | issue = 12 | pages = 1323–5 | date = December 2008 | pmid = 19008928 | doi = 10.1038/ni1208-1323 | s2cid = 6691974 }}</ref>

==Memory T cell==
{{main|Memory T cell}}
Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers.<ref>{{cite journal | vauthors = Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A | title = Two subsets of memory T lymphocytes with distinct homing potentials and effector functions | journal = Nature | volume = 401 | issue = 6754 | pages = 708–712 | date = October 1999 | pmid = 10537110 | doi = 10.1038/44385 | s2cid = 4378970 | bibcode = 1999Natur.401..708S }}</ref> Central memory T cells reside in the lymph nodes while effector memory T cells lack the [[C-C chemokine receptor type 7]] (CCR7) and [[L-selectin]] (CD62L) receptors, which prevents them from trafficking to the lymph nodes.

Additional populations of memory T cells are now known to exist.  These include tissue-resident memory T (Trm) cells and virtual memory T cells.<ref>{{cite journal | vauthors = Marusina AI, Ono Y, Merleev AA, Shimoda M, Ogawa H, Wang EA, Kondo K, Olney L, Luxardi G, Miyamura Y, Yilma TD, Villalobos IB, Bergstrom JW, Kronenberg DG, Soulika AM, Adamopoulos IE, Maverakis E | display-authors = 6 | title = CD4<sup>+</sup> virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity | journal = Journal of Autoimmunity | volume = 77 | issue = 2 | pages = 76–88 | date = February 2017 | pmid = 27894837 | pmc = 6066671 | doi = 10.1016/j.jaut.2016.11.001 }}</ref>  The single unifying theme for all memory T cell subtypes is that they are long-lived and can expand quickly to large numbers of effector T cells upon encountering their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens.

== Role in disease ==
Considering the diverse and important role helper T cells play in the immune system, it is not surprising that these cells often influence the immune response against disease. They also occasionally generate non-beneficial responses. Very rarely, the helper T cell response could lead to the death of the host.{{Citation needed|date=October 2022}}

=== Antitumor immunity ===
{{Main|CD4+ T cells and antitumor immunity}}

=== Hypersensitivity ===
The immune system must achieve a balance of sensitivity in order to respond to foreign antigens without responding to the antigens of the host itself. When the immune system responds to very low levels of antigen that it usually shouldn't respond to, a [[hypersensitivity]] response occurs. Hypersensitivity is believed to be the cause of [[allergy]] and some [[auto-immune disease]].

Hypersensitivity reactions can be divided into four types:
* [[Type 1 hypersensitivity]] includes common immune disorders such as [[asthma]], [[allergic rhinitis]] (hay fever), [[eczema]], [[urticaria]] (hives) and [[anaphylaxis]]. These reactions all involve [[IgE]] [[antibody|antibodies]], which require a T<sub>h</sub>2 response during helper T cell development. Preventive treatments, such as [[corticosteroids]] and [[montelukast]], focus on suppressing mast cells or other allergic cells; T cells do not play a primary role during the actual inflammatory response. It's important to note that the numeral allocation of hypersensitivity "types" does not correlate (and is completely unrelated) to the "response" in the T<sub>h</sub> model.
* [[Type II hypersensitivity|Type 2]] and [[Type 3 hypersensitivity]] both involve complications from auto-immune or low affinity antibodies. In both of these reactions, T cells may play an accomplice role in generating these auto-specific antibodies, although some of these reactions under Type 2 hypersensitivity would be considered normal in a healthy immune system (for example, [[Rhesus factor#Hemolytic disease of the newborn|Rhesus factor reactions]] during child-birth is a normal immune response against child antigens). The understanding of the role of helper T cells in these responses is limited but it is generally thought that T<sub>h</sub>2 cytokines would promote such disorders. For example, studies have suggested that [[Lupus erythematosus|lupus]] (SLE) and other auto-immune diseases of similar nature can be linked to the production of T<sub>h</sub>2 cytokines.
* [[Type 4 hypersensitivity]], also known as [[Hypersensitivity#Coombs and Gell classification|delayed type hypersensitivity]], are caused via the over-stimulation of immune cells, commonly [[lymphocytes]] and [[macrophages]], resulting in chronic [[inflammation]] and cytokine release. Antibodies do not play a direct role in this allergy type. T cells play an important role in this hypersensitivity, as they activate against the stimulus itself and promote the activation of other cells; particularly macrophages via T<sub>h</sub>1 cytokines.

Other cellular hypersensitivities include [[cytotoxic T cell]] mediated [[auto-immune disease]], and a similar phenomenon; [[transplant rejection]]. Helper T cells are required to fuel the development of these diseases. In order to create sufficient [[Autoimmunity|auto-reactive]] killer T cells, [[interleukin-2]] must be produced, and this is supplied by CD4<sup>+</sup> T cells. CD4<sup>+</sup> T cells can also stimulate cells such as [[natural killer cell]]s and macrophages via cytokines such as [[interferon-gamma]], encouraging these cytotoxic cells to kill host cells in certain circumstances.

The mechanism that killer T cells use during auto-immunity is almost identical to their response against [[viruses]], and some viruses have been accused of causing auto-immune diseases such as [[Diabetes mellitus type 1|Type 1 diabetes mellitus]]. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the [[immune system]] believes, by mistake, that a host antigen is foreign. As a result, the CD8<sup>+</sup> T cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen.

Some of this section is a simplification. Many auto-immune diseases are more complex. A well-known example is [[rheumatoid arthritis]], where both antibodies and immune cells are known to play a role in the pathology. Generally the immunology of most auto-immune diseases is not well understood.

=== HIV infection ===
Perhaps the best example of the importance of [[CD4|CD4<sup>+</sup>]] T cells is demonstrated with [[HIV|human immunodeficiency virus]] (HIV) infection. HIV mainly targets lymphoid CD4<sup>+</sup> T cells, but can infect other cells that express CD4 such as [[macrophages]] and [[dendritic cells]] (both groups express CD4 at low levels).{{cn|date=June 2022}}

It has been proposed that during the non-symptomatic phase of HIV infection, the virus has a relatively low affinity towards T cells (and has a higher affinity for macrophages), resulting in a slow kill rate of CD4<sup>+</sup> T cells by the immune system.{{Citation needed|date=March 2013}} This is initially compensated for via the production of new helper T cells from the [[thymus]] (originally from the [[bone marrow]]). Once the virus becomes [[HIV#Tropism|lymphotropic]] (or T-tropic) however, it begins to infect CD4<sup>+</sup> T cells far more efficiently (likely due to a change in the [[co-receptor]]s it binds to during infection), and the immune system is overwhelmed. Studies suggest that only ~5% of the lymphoid-derived CD4 T cells targeted by HIV are permissive and become productively infected with the virus. More than 95% of the CD4 T cells that die are resting and are unable to support productive infection. These cells undergo abortive infection with HIV.<ref>{{cite journal | vauthors = Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, Hebbeler AM, Greene WC | display-authors = 6 | title = Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue | journal = Cell | volume = 143 | issue = 5 | pages = 789–801 | date = November 2010 | pmid = 21111238 | pmc = 3026834 | doi = 10.1016/j.cell.2010.11.001 }}</ref> Cell death is triggered when the host cell detects HIV foreign DNA intermediates and initiates a suicidal death pathway in an attempt to protect the host, leading to [[caspase-1]] activation in [[inflammasome]]s, thus causing [[pyroptosis]] (a highly inflammatory form of programmed cell death).<ref name="Doitsh_2014">{{cite journal | vauthors = Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC | display-authors = 6 | title = Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection | journal = Nature | volume = 505 | issue = 7484 | pages = 509–514 | date = January 2014 | pmid = 24356306 | pmc = 4047036 | doi = 10.1038/nature12940 | bibcode = 2014Natur.505..509D }}</ref><ref>{{cite journal | vauthors = Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC | title = IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV | journal = Science | volume = 343 | issue = 6169 | pages = 428–432 | date = January 2014 | pmid = 24356113 | pmc = 3976200 | doi = 10.1126/science.1243640 | bibcode = 2014Sci...343..428M }}</ref><ref>{{cite journal | vauthors = Zhang C, Song JW, Huang HH, Fan X, Huang L, Deng JN, Tu B, Wang K, Li J, Zhou MJ, Yang CX, Zhao QW, Yang T, Wang LF, Zhang JY, Xu RN, Jiao YM, Shi M, Shao F, Sékaly RP, Wang FS | display-authors = 6 | title = NLRP3 inflammasome induces CD4+ T cell loss in chronically HIV-1-infected patients | journal = The Journal of Clinical Investigation | volume = 131 | issue = 6 | date = March 2021 | article-number = e138861 | pmid = 33720048 | pmc = 7954596 | doi = 10.1172/JCI138861 | doi-access = free }}</ref>

At this point chronic inflammation ensues, and functional CD4<sup>+</sup> T cell levels begin to decrease, eventually to a point where the CD4<sup>+</sup> T cell population is too small to recognize the full range of [[antigen]]s that could potentially be detected. The depletion of CD4 T cells and the development of chronic inflammation are signature processes in HIV pathogenesis that propel progression to acquired immune deficiency syndrome (AIDS). CD4 T cell depleted to the cell count of less than 200cell/μL in blood during AIDS allows various [[pathogens]] to escape T cell recognition, thus allowing [[opportunistic infection]]s that would normally elicit a helper T cell response to bypass the immune system.<ref>{{Cite web|title = CD4 Count|url = https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/understand-your-test-results/cd4-count/|website = www.aids.gov|access-date = 2015-04-30|archive-date = 2015-04-15|archive-url = https://web.archive.org/web/20150415033514/https://aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/understand-your-test-results/cd4-count/}}</ref> While these complete bypass situations only occur when the helper T cell response is absolutely necessary for infection clearance, most infections increase in severity and/or duration because the immune system's helper T cells provide less efficient immune response.

Two components of the immune system are particularly affected in AIDS, due to its CD4<sup>+</sup> T cell dependency:

# [[Cytotoxic T cell|CD8]]<sup>+</sup> T cells are not stimulated as effectively during the AIDS stage of HIV infection, making AIDS patients very susceptible to most viruses, including HIV itself. This decline in killing of CD4<sup>+</sup> T cells results in the virus being produced for a longer period (the infected CD4<sup>+</sup> T cells are not killed as quickly), increasing the proliferation of the virus, and accelerating the development of the disease.
# [[Antibody class switching]] declines significantly once helper T cell function fails. The immune system loses its ability to improve the affinity of their antibodies, and are unable to generate B cells that can produce antibody groups such as [[Immunoglobulin G|IgG]] and [[Immunoglobulin A|IgA]]. These effects are primarily due to the loss of any helper T cell that can interact with the B lymphocyte correctly. Another symptom of AIDS is the reduction in antibody levels due to a decrease in T<sub>h</sub>2 cytokines (and less interactions by helper T cells). All of these complications result in an increased susceptibility to aggressive bacterial infections, especially in areas of the body not accessible by [[Immunoglobulin M|IgM]] antibodies.

If the patient does not respond to (or does not receive) [[Management of HIV/AIDS|HIV treatment]] they will succumb usually to either cancers or infections; the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with the disease.

Inhibition of CD4 T-cell expansion during HIV infection may occur due to microbial translocation in an IL-10-dependent way. Triggering PD-1 expressed on activated monocytes by its ligand PD-L1, induces IL-10 production which inhibits CD4 T-cell function.<ref>{{cite journal | vauthors = Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP | display-authors = 6 | title = Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection | journal = Nature Medicine | volume = 16 | issue = 4 | pages = 452–459 | date = April 2010 | pmid = 20208540 | pmc = 4229134 | doi = 10.1038/nm.2106 }}</ref>

=== COVID-19 ===
In [[coronavirus disease 2019]] (COVID-19) [[B cell]], [[natural killer cell]], and total [[lymphocyte]] counts decline, but both CD4<sup>+</sup> and CD8<sup>+</sup> cells decline to a far greater extent.<ref name="pmid32542842">{{cite journal | vauthors = Huang W, Berube J, McNamara M, Saksena S, Hartman M, Arshad T, Bornheimer SJ, O'Gorman M | display-authors = 6 | title = Lymphocyte Subset Counts in COVID-19 Patients: A Meta-Analysis | journal = Cytometry. Part A | volume = 97 | issue = 8 | pages = 772–776 | date = August 2020 | pmid = 32542842 | pmc = 7323417 | doi = 10.1002/cyto.a.24172 }}</ref> Indicating that [[SARS-Cov-2]] attacks the CD4<sup>+</sup> cells during infection. Low CD4<sup>+</sup> predicted greater likelihood of [[intensive care unit]] admission, and CD4<sup>+</sup> cell count was the only parameter that predicted length of time for viral [[RNA]] clearance.<ref name="pmid32542842" /> Despite the reduced levels of CD4<sup>+</sup>, COVID-19 patients with severe disease had higher levels of T<sub>h</sub>1 CD4<sup>+</sup> cells than patients with moderate disease.<ref name="pmid32807916">{{cite journal | vauthors = Perlman S | title = COVID-19 poses a riddle for the immune system | journal = Nature | volume = 584 | issue = 7821 | pages = 345–346 | date = August 2020 | pmid = 32807916 | doi = 10.1038/d41586-020-02379-1 | doi-access = free }}</ref> It is noted that SARS-Cov-2 does [[reverse transcriptase]] like HIV against these cells.<ref name="pmid32807916">{{cite journal | vauthors = Perlman S | title = COVID-19 poses a riddle for the immune system | journal = Nature | volume = 584 | issue = 7821 | pages = 345–346 | date = August 2020 | pmid = 32807916 | doi = 10.1038/d41586-020-02379-1 | doi-access = free }}</ref>

== See also ==
* [[CD4+/CD8+ ratio|CD4<sup>+</sup>/CD8<sup>+</sup> ratio]]
* [[CD4+ T cells and antitumor immunity|CD4<sup>+</sup> T cells and antitumor immunity]]
* [[Cytotoxic T cell|CD8<sup>+</sup> T cells]]
* [[Cancer vaccine targeting CD4+ T cells|Cancer vaccine targeting CD4<sup>+</sup> T cells]]
* [[List of distinct cell types in the adult human body]]

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Doitsh G, Greene WC | title = Dissecting How CD4 T Cells Are Lost During HIV Infection | journal = Cell Host & Microbe | volume = 19 | issue = 3 | pages = 280–291 | date = March 2016 | pmid = 26962940 | pmc = 4835240 | doi = 10.1016/j.chom.2016.02.012 }}
* {{cite journal | vauthors = Kanno Y, Vahedi G, Hirahara K, Singleton K, O'Shea JJ | title = Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity | journal = Annual Review of Immunology | volume = 30 | pages = 707–731 | year = 2012 | pmid = 22224760 | pmc = 3314163 | doi = 10.1146/annurev-immunol-020711-075058 }}
{{refend}}

== External links ==
{{Commons category}}
* {{cite web |url= http://www.tcells.org/scientific/helper/ |title= T-cell Group |publisher= [[Cardiff University]] |website= T-Cells }}

{{Lymphocytes}}
{{Lymphocytic immune system}}

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