The functional role of AIRE-dependent regulatory T cells in the maintenance of immune tolerance to peripheral antigens
Final Report Abstract
CD4+ Foxp3+ regulatory T cells (Tregs) are critical for the regulation of immune homeostasis, organ-specific tolerance, and immune responses to both foreign and self-antigens by suppressing the proliferation and cytokine production in different subsets of immune cells. Previously, we have identified a population of naturally occurring Tregs (named MJ23) expressing a conserved T cell receptor (TCR) ap that is highly enriched by antigen-driven selection in mice with prostate cancer. With this model system, we were able to investigate, for the very first time, a naturally occurring tumor-associated Treg population with respect to its development, antigen specificity, and life cycle. In brief, our studies revealed that MJ23 Tregs are not reactive to a tumor-specific antigen and that the development of a naturally derived (MJ23) Treg specificity is dependent on the transcriptional regulator Aire. Within the thymus, Aire is expressed by medullary thymic epithelial cells (mTECs), where it promotes the expression of tissue-specific selfantigens and contributes to the induction of immunological tolerance to peripheral organs. The objectives of this proposal were to elucidate the functional role of Airedep Tregs to suppress autoimmunity by self-reactive T cells at peripheral sites, and to determine the prevalence of Airedep Tregs within the peripheral Treg repertoire. The central hypothesis of this proposal was that Airedep Tregs constitute a specific Treg pool, possessing special features, with a TCR repertoire that is distinct from that of Aire'nd Tregs, and serve critical functions in peripheral tolerance to organ specific antigens. To date, Aire-dependent processes are thought to promote both clonal deletion and the development of Foxp3+ regulatory T cells (Tregs), suggesting that autoimmunity associated with Aire deficiency results from two failed tolerance mechanisms. However, examination of the T cells infiltrating autoimmune lesions in Aire-' mice reveals an unexpected third possibility. We find that the predominant conventional T cell clonotypes infiltrating target lesions express antigen receptors that are preferentially expressed by Foxp3+ Treg cells in Aire+/+ mice, suggesting that autoimmune pathology is driven by the diversion of Treg clonotypes into pathogenic conventional T cells. Thus, Aire enforces immune tolerance by ensuring the proper differentiation of distinct autoreactive T cell specificities into the Treg lineage, thereby simultaneously removing these “T-rogue” clones from the conventional T cell repertoire. The results of this project furthermore provide explanations for the CD4+ T cell dependency of Aire-associated pathology, bringing clarity to this long-standing question and may reveal new targets for immunotherapies directed against autoimmune diseases and cancer.
Publications
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“Aire Enforces Immune Tolerance by Directing Autoreactive T Cells into the Regulatory T Cell Lineage”, Immunity 44(5), May 2016
Malchow, Sven; Leventhal, Daniel S.; Lee, Victoria; Nishi, Saki; Socci, Nicholas D. & Savage, Peter A.
