PTPN22 IN T1D · Effect of PTPN22 on Treg to Teff equilibrium in human and murine autoimmune diabetes

Effect of PTPN22 on Treg to Teff equilibrium in human and murine autoimmune diabetes

My research funded by the Marie-Curie Integration Grant has been focused on deciphering the role of Ptpn22, a gene associated with increased susceptibility to type 1 diabetes (T1D), in immune responses toward self, allogeneic and viral antigens. As of today, T1D ranks as one of the most autoimmune diseases in the western world. T1D is a metabolic disease that results from T cell-mediated destruction of the insulin-producing beta cells of the pancreas. While the aetiology of T1D remains unknown, genetic linkage studies support a critical role for genetic and environmental factors that act in sync at initiating and precipitating disease onset. T1D can result from defective checkpoints in the development of self-reactive T and B cells, where antigen receptor signaling is involved. For example, T1D can be caused by aberrant activation of T helper cells, or the impaired development and function of T regulatory (Treg) cells. While several genetic factors are likely to underlie the defects in the aforementioned control points, the autoimmune-risk variant R620W of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) has emerged as key genetic modifier of T and B cell receptor signaling. Consequently, the PTPN22 R620W risk allele encoding a gain-of-function variant is associated with an increased risk for the development of several autoimmune diseases, including T1D. In our studies, we tested whether the autoimmune predisposing allele of PTPN22 affects the generation of FOXP3+ Treg cells and T helper type 1 (Th1) cells in mice and humans. To do so, murine CD4 T cells were isolated from PTPN22-deficient mice and cultured in Treg or Th1 cell polarizing conditions in vitro. Similarly, human CD4 T cells from healthy donors and patients with T1D were differentiated towards FOXP3 Treg in vitro. To knock-down the expression of PTPN22 in the human studies, specific PTPN22 anti-sense oligonucleotides were used. We found that PTPN22 is a key factor in setting the proper threshold for T-cell activation and consequently FOXP3 Treg cell differentiation in both mice and humans, whereas it is dispensable for Th1 differentiation. Our findings extend previous observations and propose new mechanisms for autoimmune predisposition by PTPN22. The findings of this study can be found at: http://www.ncbi.nlm.nih.gov/pubmed/24905474 We performed additional studies in murine models of T1D and pancreatic islet transplantation where we deciphered the role of PTPN22 in immune responses to self, allogeneic and viral antigens. More specifically: • By crossing the transgenic model RIP-LCMV with Ptpn22-deficient mice, we showed that lack of PTPN22 exacerbates virally-induced T1D. We additionally examined the LCMV-specific antiviral CD4 and CD8 T cell responses at the expansion, contraction and memory phase of the immune response, and found that lack of PTPN22 largely augmented the antiviral effector T cell responses. These results suggest that therapeutic strategies targeting PTPN22 should be treated with caution as they might enhance anti-viral immune responses. The findings of this study can be found at: http://www.ncbi.nlm.nih.gov/pubmed/25513733 • We also identified PTPN22 as key regulator of type 1 regulatory (Tr1) cell homeostasis and function in addition to FOXP3 Treg cells, with immediate implications for transplant tolerance. We found that in a mouse model of pancreatic islet transplantation, lack of PTPN22 increased the number of alloreactive T cells but did not alter the kinetics of allograft rejection. Although the absence of PTPN22 increased the overall frequency of FOXP3 Treg cells, PTPN22-deficient mice displayed resistance to allograft rejection after Treg cell depletion due to augmented frequency and number of Tr1 cells. Furthermore, increased transplant tolerance could be achieved in PTPN22-/- mice following treatment with an established immunomodulatory therapy, through the recompensed action of both FOXP3 Treg and Tr1 cells. Therefore, these findings extend previous studies, and establish PTPN22 as key regulator of transplant tolerance. The findings of this study can be found at: http://www.ncbi.nlm.nih.gov/pubmed/25748328 During these years I established expertise in the field of PTPN22 and was invited to submit a review article. In this review, the role of PTPN22 in T, B and innate immune cells is summarized (http://www.ncbi.nlm.nih.gov/pubmed/24269925). The scientific community acknowledged the importance of our findings by selecting my submitted abstracts for oral presentation in several well-known international scientific meetings, i.e. FOCiS, IDS. For further information, I can be contacted at fousteri.georgia@hsr.it

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