Tolerance Induction in Recent Thymic Emigrants

Recent thymic emigrants (RTEs) comprise the subset of T cells that have most recently undergone thymic maturation and egress to the lymphoid periphery. RTEs are an important lymphocyte population to study because they represent the majority of T cells in neonates and contribute to T cell diversity throughout life. Using RAG2p-GFP transgenic mice to identify RTEs, our lab has discovered that T cell development, once thought to be completed within the thymic microenvironment, continues for several weeks after cells have left the thymus and entered the lymphoid periphery. While it is now appreciated that post-thymic maturation is the norm, it remains unclear what advantages are provided to the individual by the export of T cells that interpret and respond to their immunological environment in a manner so distinct from that of their mature, but still naive counterparts. We hypothesized that post-thymic maturation entails a T cell developmental period that facilitates tolerance induction to peripheral antigens, both self and commensal-derived, not previously encountered during thymic development. Using a well-established mouse model of peripheral self-antigen, we show here that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which RTEs encounter antigen. Following encounter with TRAs in the absence of inflammation, RTEs exhibited defects in proliferation, diminished cytokine production, elevated expression of anergy-associated genes, and diminished ability to cause diabetes. These properties were mirrored in vitro by enhanced RTE susceptibility to regulatory T cell-mediated suppression. In the presence of inflammation, RTEs and mature T cells were, in contrast, equally capable of inducing diabetes, proliferating, and producing cytokines. Thus, recirculating RTEs encounter TRAs during a transitional developmental stage that facilitates tolerance induction, but inflammation converts antigen-exposed, tolerance-prone RTEs into competent effector cells.