Fine-tuning of T lymphocyte-differentiation by peripheral regulatory T cells recirculating back to the thymus – TregThymus

By suppressing immune-responses, regulatory T lymphocytes (Treg) expressing the transcription factor Foxp3 play a vital role in protecting the organism against autoimmune disease and other types of immunopathology. The high level of sophistication of control by Treg bestows them with substantial potential in the treatment of a large variety of diseases and clinical trials using these cells are on-going.

The majority of Treg is produced in the thymus where their precursors differentiate and undergo rigorous selection processes according to their antigen-specificity, key in the prevention of autoimmune disorders. The thus selected Treg-population enriched in autospecific cells migrates to “the periphery” where it exerts its immunosuppressive activities. Intriguingly, we recently demonstrated that activated peripheral Treg can re-enter the thymus in mice and humans. We showed that recirculating Treg inhibit the development of their precursors. Importantly, the proportion of recirculating cells among Treg considerably increases with age.

We here propose to study the functional consequences of the re-entry of mature activated Treg into the thymus and its potential implication in the development of immunopathology.

In the periphery, Treg interfere, in an antigen-specific manner, with cells that present antigen to T cells, leading to inactivation of the antigen-presenting cells and thus to their incapacity to activate T lymphocytes. Our preliminary data indicate that Treg recirculating to the thymus similarly interfere with stromal cells and thus modify their capacity to select the repertoire of antigen-receptors expressed by developing T lymphocytes. We here propose to consolidate this intriguing observation by analysing the mechanisms involved in the intrathymic migration of recirculating Treg, their interaction with thymic stromal cells, and the consequences on the function of stromal cells. We will further assess the influence of recirculating Treg on T cell repertoire-selection by studying the development of T cells with known antigen-specificity using in vitro thymus organ cultures. We reported that recirculating Treg inhibit interleukin 2-dependent but not -independent Treg differentiation, induced by distinct types of thymic stromal cells with distinct functional capacities. We will therefore address the potential influence of recirculating Treg on selection by comparing the repertoires of T cell receptors for antigen expressed by Treg that developed in an interleukin 2-dependent and -independent manner (in interleukin 2-deficient mice). Using the same comparison, we will study the hypothetical consequences of Treg recirculation on the functional potential of developing Treg. We have recently observed that Treg recirculation to the thymus is strongly enhanced in autoimmune-prone mice, suggesting that it is linked to their susceptibility to develop immunopathology. We will address this hypothesis by studying the causes of increased Treg recirculation and the consequences of this process on development of the Treg repertoire and on the susceptibility of autoimmune-prone mice to pathology.

We feel that the novel concept of recirculation of peripheral mature Treg back to the thymus merits thorough investigation; its originality constitutes a solid basis for breakthrough fundamental research, its probable capacity to interfere with thymic selection mechanisms is intriguing, its potential involvement in immunopathology represents a new opportunity to discover pathophysiological mechanisms. Our project will allow for a thorough analysis of the causes and consequences of the recirculation of mature activated Treg back to the thymus using novel and powerful technology, data processing, and mathematical models.