Protein tyrosine phosphatase non-receptor type 22 is a cytoplasmatic protein encoded by gene PTPN22 and a member of PEST family of protein tyrosine phosphatases. This protein is also called "PEST-domain Enriched Phosphatase" ("PEP") or "Lymphoid phosphatase" ("LYP"). The name LYP is used strictly for the human protein encoded by PTPN22, but the name PEP is used only for its mouse homolog. However, both proteins have similar biological functions and show 70% identity in amino acid sequence. PTPN22 functions as a negative regulator of T cell receptor (TCR) signaling, which maintains homeostasis of T cell compartment.
Gene Gene PTPN22 is located on the p arm of the human chromosome 1. It is nearly 58 000 base pairs long and contains 21 exons. In the case of mouse genome, it is located on the q arm of the chromosome 3. It is nearly 55 700 base pairs long and contains 23 exons.
Structure PTPN22 is composed from 807 amino acids, and it weighs 91,705 kDa. On its N terminus it possesses catalytic domain, which shows the highest level of conservation between human and mouse proteins. Other parts of PTPN22 are less conserved. After catalytic domain PTPN22 has approximately 300 amino acids long domain called "Interdomain". On the C terminus of PTPN22 there are 4 proline-rich motifs (P1 - P4), which can mediate interactions with other proteins. P1 motif is the most important among them, because it is crucial for binding of CSK kinase, and allele encoding PTPN22 with mutated P1 motif is associated with increased risk of numerous autoimmune diseases.
Function
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, and also with the experiments of PTPN22 overexpression in vitro. 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. PTPN22 deficiency does not impair the suppressive function of Treg cells. Actually there are some articles suggesting that PTPN22-deficient Treg cells possess an enhanced suppressive function or have a bigger ability to obtain an effector phenotype.
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