Editing T helper cell (section)

=== 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}}