Regulation of T cell receptor signaling A T cell receptor activation by a cognate
peptide triggers a signaling pathway activating a T cell. The first event of this pathway is activation of the
SRC family kinase LCK by a dephosphorylation of its C terminal inhibition
tyrosine (Y505) and by a phosphorylation of its activation tyrosine (Y394). LCK then phosphorylate tyrosines in the
CD3 complex creating a docking site for the
SH2 domain of the
SYK family kinase ZAP70, which is there phosphorylated too. The Phosphorylated ZAP70 then propagate a signal from a TCR, phosphorylating other proteins and creating a multi-protein complex, which activates downstream signaling pathways. PTPN22 possess the ability to
dephosphorylate proteins included in proximal events of the TCR signaling and serves as an important negative regulator of a T cell activation. PTPN22 is able to bind the LCK with phosphorylated Y394, the phosphorylated ZAP70 and the phosphorylated ζ chain of CD3 complex. Thus, it binds molecules of a proximal TCR signaling only after their activation. PTPN22 can dephosphorylate those proteins and decrease the activating signal obtained by a T cell. Dephosphorylation of kinases LCK and ZAP70 by a PTPN22 is specific concerning the phosphorylated tyrosine in those proteins – only the Y394 of LCK and the Y493 of ZAP70 are dephosphorylated. In the absence of PTPN22, an activated T cell receive a stronger activation signal, which is reflected by a greater influx of
Ca2+ cations into the
cytosol, bigger phosphorylation of an LCK, ZAP70 and ERK and larger expansion of those
cells. The
inhibitory effect on a TCR signaling was also verified with the usage of PTPN22 inhibitor on a
Jurkat T cell line and on human primary T cells, The expression of PTPN22 is upregulated after an activation of T cells and an antigen-experienced T cell have higher expression of PTPN22 than a
naive T cell. The regulatory function of PTPN22 is particularly important during an activation by low
affinity peptides. In the absence of PTPN22, T cell cannot discriminate between strong and weak
antigens sufficiently and those T cells become more responsive, which can be detected like increased upregulation of
transcription factors and
CD69, increased
ERK phosphorylation, increased ability to expand
in vivo and to produce
cytokines. Increased responsiveness can also break the
tolerance against low affinity self-antigens and is well visible, when PTPN22-deficient T cells get into a
lymphopenic environment.
Regulation of regulatory T cells One particular population of T cells, which is influenced by a PTPN22 deficiency is the population of
regulatory T cells (Treg cells). PTPN22-deficient mice contain higher amount of Treg cells in
lymph nodes and
spleens and this difference is more visible with increasing age of mice. There is also a change of the effector Treg cells : central Treg cells ratio in favor of the effector Treg cells. PTPN22 deficiency increases abilities of Treg cells to survive,
differentiation of Treg cells from naive T cells, but not the ability to
proliferate in vivo, and it also supports transition of central Treg cells to effector Treg cells. One of the reasons, of the increased survival of PTPN22-deficient Treg cells, is that those cells have upregulated expression of
GITR, which increases their expansion
in vivo. Treatment of PTPN22-deficient mice with an anti-GITR-L blocking
antibody suppresses the expansion of Treg cells. The role of the PTPN22 in the regulation of LFA-1-mediated adhesion and motility is also supported by the observation of increased LFA-1 expression in PTPN22-/- Treg cells. It was also proposed that the interaction of PTPN22 and CSK regulate a localization of the PTPN22 and a
dissociation of this complex enables translocation of the PTPN22 to
lipid rafts of a
plasma membrane, where it can inhibit a TCR signaling. The mutant PTPN22, which is unable to bind CSK, is effectively recruited to a plasma membrane. == Regulation of PTPN22 ==