Diabetes and other autoimmune endocrine diseases
Risk for type 1 diabetes (T1D) is associated with a non-synonymous variant in the PTPN22 gene, R620W. PTPN22 is a tyrosine phosphatase which regulates TCR signaling, leading to changes in T cell activation and effector responses. We hypothesized that the PTPN22 R620W risk allele may alter the activation and differentiation of islet antigen reactive CD4 T cells in T1D, impacting their frequency and/or effector phenotypes. To assess this, we recruited 36 HLA matched T1D subjects, with equal numbers of non-risk and heterozygous risk individuals, and analyzed their islet and viral antigen-reactive CD4 T cells in peripheral blood using a CD154 activation assay coupled with multicolor flow cytometry. We calculated the frequency of islet-reactive CD4 T cells and analyzed their phenotypic profile using unbiased multidimensional flow cytometry analysis with flowSOM. We found that T1D patients carrying the PTPN22 risk allele had more islet-reactive CD4 T cells earlier in disease compared to non-risk subjects. Overall the islet-reactive CD4 T cells were less mature (predominantly naive, stem cell memory (TSCM)) than viral-reactive cells (effector memory, central memory). Further, the phenotypes of antigen-specific T cells differed between subjects based on PTPN22 genotype; PTPN22 risk patients had more TSCM phenotypes amongst islet-reactive T cells, with expression of activation markers and inhibitory receptors, while non-risk patients had more CD4 T effector memory/Th1 phenotypes amongst viral-reactive cells. Our findings demonstrate that the PTPN22 risk allele influences the frequency and phenotypes of islet-reactive CD4 T cells in T1D favoring activation and expansion of TSCM-like cells.