Thymic atrophy creates holes in Treg-mediated immuno-regulation via impairment of an antigen-specific clone

Rachel Thomas, Jiyoung Oh, Weikan Wang, Dong Ming Su

Research output: Contribution to journalArticlepeer-review

Abstract

Age-related thymic atrophy results in reduced output of naïve conventional T (Tcon) cells. However, its impact on regulatory T (Treg) cells is insufficiently understood. Given evidence that thymic Treg (tTreg) cell generation is enhanced in the aged, atrophy thymus and that the aged periphery accumulates peripheral Treg (pTreg) cells, we asked why these Treg cells are unable to effectively attenuate increased autoreactivity-induced chronic inflammation in the elderly. We designed a mock-self-antigen chimera mouse model, in which membrane-bound ovalbumin (mOVA) transgenic mice, bearing a FoxN1-floxed gene for induction of conditional thymic atrophy, received OVA-specific (OT-II) T-cell receptor (TCR) transgenic progenitor cells. The chimeric mice with thymic atrophy exhibited a significant decrease in OVA-specific tTreg and pTreg cells but not polyclonal (pan)-Treg cells. These OVA-specific pTreg cells were significantly less able to suppress OVA-specific stimulation-induced proliferation in vitro and exhibited lower FoxP3 expression. Additionally, we conducted preliminary TCR repertoire diversity sequencing for Treg cells among recent thymic emigrants (RTEs) from RagGFP-FoxP3RFP dual-reporter mice and observed a trend for decreased diversity in mice with thymic atrophy compared to littermates with normal thymus. These data indicate that although the effects of age-related thymic atrophy do not affect pan-Treg generation, certain tissue-specific Treg clones may experience abnormal agonist selection. This, combined with enhanced pan-pTreg cells, may greatly contribute to age-related chronic inflammation, even in the absence of acute autoimmune disease in the elderly.

Original languageEnglish
JournalImmunology
DOIs
StateAccepted/In press - 2021

Keywords

  • Treg TCR repertoire diversity
  • ageing
  • inflammaging
  • involution
  • regulatory T cell
  • thymic atrophy

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