PTPN22 Alters the Development of Regulatory T Cells in the Thymus

Abstract

PTPN22 encodes a tyrosine phosphatase that inhibits Src-family kinases responsible for antigen receptor signaling in lymphocytes, and is strongly linked with susceptibility to a number of autoimmune diseases. As strength of TCR signal is critical to the thymic selection of regulatory T cells (Tregs) we examined the effect of murine PTPN22 deficiency on Treg development and function. In the thymus, numbers of pre-Tregs and Tregs increased inversely with the level of PTPN22. This increase in Tregs persisted in the periphery and could play a key part in the reduced severity observed in the PTPN22 deficient mice of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This could explain the lack of association of certain autoimmune conditions with PTPN22 risk alleles.

A Functional Polymorphism of Ptpn22 Is Associated with Type 1 Diabetes in the BioBreeding Rat

“…The relative decrease in Tregs found in congenic animals expressing the BBDP Ptpn22 allele is different from the observation of enhanced development and function of Tregs expressing the Ptpn22 619W variant (13,14). This may be attributed to several factors, in particular the potential influence of the Gimap5 mutation on rat chromosome 4 that causes the T lymphopenia observed in the BBDP strain (2).…”

“…NOD mice are known to have a defect in Treg function at least in part because of their IL-2 allele (41). Consequently, the observation by Zheng et al (40) could be explained by the findings that the loss of Ptpn22 in mice results in increased proportions of Tregs and/or improved suppressive function of these cells (13,14). These two features could have compensated the Treg defect induced by allelic variation at the Il2 locus, and consequently inhibit the diabetogenic process in NOD mice.…”

“…Analysis of Ptpn22 2/2 murine models has shown the regulatory impact of this gene on the development and function of CD4 + CD25 + Foxp3 + Tregs (13,14). Therefore, this T cell subset was evaluated in Ptpn22 congenic 2BAa and 2BAb rat donors.…”

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

“…PEP and LYP share 89% identity at the PTP domain, and 61% identity in the non-catalytic domains. The majority of these studies have been performed in mice where the Ptpn22 gene is knocked out [18][19][20], but more recently, a model in which Ptpn22 is inducibly knocked down has also been described [21]. Ptpn22 deficiency has been shown to enhance signaling through the TCR, as measured by calcium flux and phosphorylation of LCK, ZAP70, and extracellular signal-regulated kinase (ERK) (Table 1) [15,18].…”

“…They also result in increased proliferation of effector T cells and a general expansion of the T cell compartment over time. Regulatory T cells (Tregs) are also altered in these animals, with increased Treg number, IL-10 production, and suppressive function [19,20]. Ptpn22 deficiency has also been shown to cause an expansion of germinal centers and an increase of immunoglobulin production [18].…”