Enhanced PI3K/AKT/mTOR responses are associated with resistance to activation-induced cell death and expansion of memory CD4+ T cells in T1D subjects and healthy carriers of the PTPN22 risk variant

Abstract

Abstract The genetic variant PTPN22 1858T, encoding Lyp620W, confers increased risk for multiple autoimmune diseases including Type 1 diabetes (T1D). To date, Lyp620W has been associated with increased CD4+memory T cells and enhanced Th1 responses in healthy carriers. However, it is not clear whether this is due to altered lineage commitment and/or survival within the CD4+memory T cell compartment. Here, we determined the mechanism by which Lyp620W alters human CD4+memory T cell homeostasis in PTPN22 1858T carriers and T1D subjects. T1D subjects displayed significantly increased CD4+ memory T cells as compared to healthy individuals irrespective of PTPN22 genotype, which was further increased in homozygous carriers of PTPN22 1858T, suggesting a partial role for this variant. Among healthy 1858T carriers, we found a significant increase in the magnitude of Th1 effector responses, but not enhanced Th1 differentiation. Consistent with increased survival, TCR-induced PI3K/AKT/mTOR pathway responses and BCL-2 expression were augmented in CD4+ memory T cells from healthy 1858T carriers. Importantly, these alterations were associated with increased resistance to TCR-mediated apoptosis in CD4+ memory T cells. Similar changes in PI3K/AKT signaling and T cell survival were observed in the Th1 memory compartment of T1D individuals, and selective inhibition of PI3Kδ reversed the survival phenotypes in memory T cells from both healthy 1858T carriers and T1D subjects. Thus, our combined findings reveal a novel immune ‘signature’ associated with Lyp620W and highlight a clinically-relevant T cell intrinsic mechanism that promotes the survival of potentially pathogenic Th1 effector T cells in T1D.