No abstract

Co-transplantation of MSCs may lead to improved islet function and survival in the early post-transplantation period in humans receiving islet transplantation.

CD4+CD25+FOXP3+ regulatory T cells (Tregs) control the activation and expansion of alloreactive and autoreactive T cell clones. Because uncontrolled activation and expansion of autoreactive T cells occur in an IL-7–rich environment, we explored the possibility that IL-7 may affect the function of Treg. We show that the functional high-affinity IL-7R is expressed on both naive and memory Tregs, and exposure to IL-7 results in STAT-5 phosphorylation. Naive, but not memory, Tregs proliferated greatly and acquired a memory phenotype in the setting of a suppression assay when IL-7 was present. Importantly, the presence of IL-7 abrogated the capacity of Tregs to suppress proliferation of conventional T cells in response to TCR activators, including alloantigens and autoantigens. Removal of IL-7 restored the suppressive function of Tregs. Preblocking of the IL-7R on the Tregs also restored suppressor function, indicating that IL-7 directly affected Treg function. Thus, prolonged periods of homeostatic expansion can temporarily release natural regulatory brakes on T cells, thereby providing an additional mechanism for activating and expanding alloreactive and autoreactive T cells.

Autoimmune diabetes is marked by sensitization to β cell self-antigens in childhood. We longitudinally followed at-risk children from infancy and performed single-cell gene expression in β cell antigen-responsive CD4 T cells through pre- and established autoimmune phases. A striking divergence in the gene signature of β cell antigen-responsive naïve CD4 T cells from children who developed β cell autoimmunity was found in infancy, well before the appearance of β cell antigen-specific memory T cells or autoantibodies. The signature resembled a pre-T helper 1 (T1)/T17/T follicular helper cell response with expression of ,, ,, ,, , and, in the absence of ,, and other cytokines. The cells transitioned to an -T1 memory phenotype with the emergence of autoantibodies. We suggest that the divergent naïve T cell response is a consequence of genetic or environmental priming during unfavorable perinatal exposures and that the signature will guide future efforts to detect and prevent β cell autoimmunity.