Homeostatic expansion permits T cells to re-enter the thymus and deliver antigen in a tolerogenic fashion.

We previously have shown that delivery of alloantigen on T cells can be used to induce tolerance through central deletion. Here, we analyzed the requirements for tolerance induced by T cells. Adoptively transferred allogeneic T cells undergo extensive homeostatic proliferation in the periphery of lethally irradiated hosts receiving a syngeneic bone marrow transplant, and acquire a memory-like cell surface phenotype. Analysis of the kinetics of thymic re-entry of transferred T cells revealed that T cells undergo homeostatic proliferation in the periphery prior to re-entry into the thymus. Prevention of homeostatic proliferation results in a failure of transferred T cells to re-enter the thymus. In the absence of homeostatic proliferation, adoptively transferred T cells were unable to induce tolerance. These date suggest that homeostatic proliferation of T cells resulting in an activated cell surface phenotype is required for thymic re-entry and is mechanistically linked to the ability of T cells to induce tolerance.