Editing T helper cell (section)

=== 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.