The functional role of AIRE-dependent regulatory T cells in the maintenance of immune tolerance to peripheral antigens

• Applicant: Dr. Sven Malchow
• Subject Area: Immunology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244784859

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. In order to develop effective Treg therapies and reduce the risk of catastrophic systemic side-effects, it is essential to elucidate the fundamental nature of endogenous Tregs, to determine the prevalence and behavior of single specificities within the polyclonal Treg population, and to identify the (auto-)antigens of endogenous Tregs. Previously, we have identified a population of naturally occurring Tregs (named MJ23) expressing a conserved T cell receptor (TCR) 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 self-antigens and contributes to the induction of immunological tolerance to peripheral organs. Mutations in AIRE are associated with the polyglandular human autoimmune disease APECED/APS-1 and Aire-deficient mice, like APECED patients, develop a multi-organ autoimmune pathology. To date, the vast majority of studies analyzing the role of Aire-deficiency were mainly focused on its role to ensure effective deletion of auto reactive T cells against peripheral auto antigens. Our recent finding that Aire is critical for the thymic development of some, but not all, naturally occurring Treg specificities suggests that two subsets of endogenous Treg populations exists: those that recognize Aire-dependent antigens (Airedep Tregs), and those that recognize Aire-independent antigens (Aire-ind Tregs). The objectives of this proposal are to elucidate the functional role of Aire-dep Tregs to suppress autoimmunity by self-reactive T cells at peripheral sites, to determine the impact of extrathymic Aire-expression to maintain immue tolerance, and to determine the prevalence of Aire-dep Tregs within the peripheral Treg repertoire. The central hypothesis of this proposal is that Aire-dep Tregs constitute a specific Treg pool with a TCR repertoire that is distinct from that of Aire-ind Tregs, and serve critical functions in peripheral tolerance to organ specific antigens. The results of the proposed studies are expected to provide novel insights with implications on our fundamental understanding of Treg biology and the development of improved immunotherapies for autoimmune diseases and cancer.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Peter A. Savage, Ph.D.