Induced regulatory T cell-derived interleukin 10 is sufficient for the cure of experimental colitis (179.19)

Abstract

Abstract Induced Treg (iTreg) cells are essential for tolerance. Although in vitro derived iTreg cells can be used therapeutically in preclinical models of autoimmune disease, their stability in vivo and their mechanisms of suppression have not been examined. Here, we used a treatment model of lymphopenia-associated colitis to examine the role of IL-10 in iTreg cell function. Monotherapy with IL-10-deficient iTreg cells slowed the onset of colitis and decreased colon infiltration, but did not resolve disease. Mice treated with WT iTreg cells in combination with IL-10-deficient natural Treg (nTreg) cells survived and gained weight, even though iTreg cells were numerically disadvantaged and comprised just ~20% of all Treg cells in treated mice. Notably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome which failed to limit their pathogenic potential. The TCR repertoires of iTreg and ex-iTreg cells exhibited almost no overlap, indicating that maintenance of the iTreg pool is based on antigen specificity. These data demonstrate a potent and critical role for iTreg cell produced IL-10 that can supplant the IL-10 produced by nTreg cells and compensate for the inherent instability of the iTreg population.