CD4+ T cell tolerance to tissue-restricted self antigens

Abstract

Self antigen-specific T cell development is influenced by how the self antigen is expressed. In this thesis, I explored this concept using a novel panel of mice in which a model self antigen is conditionally expressed in different tissues. We studied the steady state development of the unmanipulated endogenous self antigen-specific CD4+ T cell repertoire under these various conditions by using peptide:MHC II tetramers. We found that in some cases, self antigen-specific T cells were deleted efficiently in the thymus, while in others, they were partially deleted in peripheral lymphoid organs. Deletion specifically affected Foxp3- conventional T cells (Tconv), and was biased towards high avidity clones in the thymus but not periphery. In contrast, Foxp3+ regulatory T cell (Treg) numbers were elevated in the periphery, and were preferentially comprised of high avidity clones. Self antigen-specific T cells surviving deletion exhibited tolerance to antigen stimulation, with Tconv cells exhibiting greater functional impairment than Tregs. Acute ablation of Tregs partially restored the proliferative ability of self antigen-specific Tconv cells, which demonstrated that, in addition to Tconv deletion, Treg development is important in maintaining tolerance. Although functionally impaired in the absence of Tregs, self-antigen specific Tconv cells did not express FR4 and CD73, which mark anergic T cells undergoing transition into peripherally induced Tregs. Genetic deficiency of Aire did not affect the peripheral deletion of self antigen-specific T cells, indicating that this process can occur independently of this transcriptional regulator. Finally, we implemented the use of cutting edge single-cell RNA-seq technology to transcriptional profile tetramer-sorted self antigen-specific T cells, and our preliminary findings revealed the development of Foxp3- IL-10 expressing type 1 regulatory T cells (Tr1) in a gut self antigen-specific T cell population. Together, our results illustrate how steady state T cell recognition of tissue-restricted self antigens results in opposing effects on Tconv and Treg subset development, both of which contribute to self tolerance.