Age-related thymic atrophy impairs development and function of an antigen-specific tTreg cell population

Purpose: The atrophied thymus generates an increased ratio of polyclonal thymic T regulatory (tTreg) cells to thymic T conventional (tTcon) cells, and peripheral Treg (pTreg) cells accumulate during aging. So, why are pTregs in the elderly unable to effectively suppress age-related inflammation ("inflammaging")? Methods: We utilized a mock self-antigen (autoimmune pancreatitis) chimeric mouse model, in which irradiated rat insulin promotor-driven (RIP) mOVA mice received mixed OT-II TCR transgenic and wild-type bone marrow. Thus, we can easily visualize the generation and activation of an antigen-specific T cell population. Additionally, our mOVA host mice carry a FoxN1-floxed gene for induction of conditional thymic atrophy, analogous to the aged thymus. Results: The chimeric mice with thymic atrophy exhibited significant decline in central and peripheral OVA-specific (OT-II) Tregs, but not total (pan) Tregs. Further, intrinsic Treg changes in FoxP3 and CD25 expression were observed, likely induced by the atrophied thymic environment. These markers remained decreased even in response to OVA stimulation, suggestive of reduced suppressive capacity. This was confirmed via functional assays showing that OVA-specific Tregs were significantly less able to suppress antigen-specific stimulation of Teffs in vitro. We suspect that thymic atrophy restricts the antigen-specific T cell receptor (TCR) repertoire during tTreg generation, so we are currently conducting TCR repertoire diversity sequencing. Conclusion: Combined with our observed functional defects, if TCR sequencing confirms a reduced tTreg TCR diversity, thymic atrophy has implications for increasing risk of autoimmune predisposition in the elderly.