Targeting CD44 ameliorates autoimmune diabetes by reducing pancreatic infiltrates and improving Treg efficacy (P5180)

Abstract

Abstract In type 1 diabetes (T1D), Th1 cells are a major population orchestrating the disease pathology. We showed previously that signals through CD44 are needed for Th1 cell survival and memory development. Therefore, we hypothesized that blocking CD44 could impact progression to overt diabetes. To test this, we treated recently hyperglycemic NOD mice with a short course of anti-CD44 and found a significant delay in the spontaneous development of TID that was associated with a reduction in islet infiltrates. However, previous studies suggested that targeting CD44 might enhance Treg function. To test whether this could contribute to the anti-CD44-mediated effect, we transferred polyclonal in vitro differentiated adaptive Treg cells (aTregs), which we showed can protect ~50% of newly hyperglycemic mice from overt diabetes, together with anti-CD44 treatment. We found a significantly increased the success rate of diabetes prevention. The islet infiltrates in these mice had a higher frequency of CD4+ cells producing IL-10 and IL-2 as well as of endogenous Tregs that displayed enhanced FoxP3 expression. However, anti-CD44 treatment did not alter cytokine profiles or Foxp3 expression of the transferred aTregs. The data therefore suggest that anti-CD44 treatment can alleviate inflammation in the target organ, and can functionally enhance the endogenous Treg population, thereby improving the establishment of long-term control by aTregs, which form a protective memory population.