Treg-restricted deletion of TRAIL (Tnfsf10) reduces autoimmune diabetes

Abstract

Abstract Regulatory T cells (Tregs) are a suppressive cell population that limit the anti-tumor response. One mechanism Tregs utilize is production of suppressive cytokines. We previously asked if deletion of the two main suppressive cytokines made by Tregs would have any overall effect on the suppressive ability of the Tregs. We found that Treg-restricted deletion of the cytokines IL-10 and IL-35 led to a compensatory upregulation of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; Tnfsf10). In these studies, upregulation of TRAIL was dependent on deletion of IL-10 and IL-35; however, we also wondered if TRAIL could also be upregulated in inflammatory environments and if deletion would affect Treg function in these environments. We made a Tnfsf10L/L mouse, backcrossed onto both B6 and NOD backgrounds, and crossed each with respective Foxp3Cre lines. Surprisingly, we found little effect on tumor growth in B6 mice but found a substantive decrease in autoimmune diabetes incidence in the NOD mouse model. In the latter, we found that Treg-restricted deletion of TRAIL may extrinsically effect CD8+ and CD4+ T cell phenotype by increasing expression of suppressive molecules such as CD73 and LAP-TGFβ in these cells. Future studies are necessary to understand if this phenotypic change is responsible for the decrease in diabetes incidence.