IL-2 Ameliorates Chronic GVHD by Inducing Antigen-Specific Regulatory T Cells.

We have developed a mouse model in which a GvHD-like syndrome develops in response to a defined soluble self-antigen. This phenotype is caused after transfer of CD4+ T cells that have a single specificity and are reactive to the self-antigen into a lymphopenic host that expresses the cognate antigen. By using a clonotypic antibody we are able to identify these cells and can therefore follow their migration, kinetics and functional characteristics. At least two distinct phases can be identified by clinical picture and correlated with accumulation of T cells - an early phase, resembling acute GvHD, leading to wasting and death coinciding with rapid accumulation of T cells, and a late phase in which a stable number of T cells is maintained clinically reminiscent of chronic GvHD. We show here that a fraction of the naïve T cells that encounter the self-antigen after transfer develop into CD4+CD25+ regulatory T cells (Treg) in the periphery. This population controls T cell homeostasis, activation and severe immune pathology. The development of CD4+CD25+ Treg critically depends on IL-2 produced by the T cells. Therefore, in the absence of IL-2, T cell homeostasis cannot be maintained and massive accumulation of CD4+ T cells leads to severe inflammation of the skin. Importantly, only IL-2 that is produced by the T cells themselves, but not from peripheral tissues, leads to efficient generation of Treg and T cell homeostasis. We suggest that Treg-development is a differentiation step of T cells that encounter self-antigen in the periphery, and is essential for maintaining homeostasis even in the presence of self-recognition. Our data provide mechanistic insight into the re-establishment of homeostasis after cell transfer into a lymphopenic host and have important implications for the use and timing of therapeutic approaches targeting the IL-2 pathway.