Editing T helper cell (section)

== 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 | pages = 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 | pages = 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. 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}}