Editing T helper cell (section)

== 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 helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as T<sub>h</sub>1 and T<sub>h</sub>2 cells (also known as Type 1 and Type 2 helper T cells, respectively).{{cn|date=April 2025}}

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 | pages = 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>