Regulatory T cells (Tregs) improve immune reconstitution after bone marrow transplant (BMT) by promoting development of more diverse TCR repertoire and reducing the incidence of graft-versus-host disease (GVHD). How Tregs mediate these effects is unknown. In order to examine the role of Tregs in regulating T cell reconstitution during lymphopaenia, we used a mouse model of lymphopaenia-induced proliferation (LIP), in which 4-6% of CD4 T cells spontaneously activate and undergo rapid division when adoptively transferred into immunodeficient Rag-/- hosts. Using this model we demonstrated that reconstitution of the Treg compartment prior to T cell transfer inhibits LIP, with CD4 T cells instead undergoing slow homeostatic division to repopulate the host with a diverse repertoire of naïve T cells. Inhibition of LIP was primarily mediated via CTLA-4-dependent downregulation of CD80/CD86 expression by DCs. Importantly, the level of CD80/CD86 was determined by the ratio of Tregs:DCs, suggesting that normalising the Treg:DC ratio rather than the Treg:Tcell ratio may be more important in promoting optimal immune reconstitution during lymphopaenia.
Recently, we tested this hypothesis in a BMT setting in which C57BL/6 BM was transplanted into lethally irradiated B10.BR hosts. Expression of CD80/CD86 by DCs was elevated post-irradiation, but could be normalised by selective reconstitution with Tregs. Both allogeneic C57BL/6 and syngeneic B10.BR Tregs were capable of mediating this effect, although syngeneic Tregs were more efficient early after irradiation due to their superior ability to reconstitute at that time. Allogeneic Tregs failed to repopulate the host if transferred at the time of BMT, but did reconstitute if transferred at day 6 or 12 post-irradiation. These differences may relate to a survival requirement for adoptively transferred Tregs to receive a TCR stimulus from syngeneic DCs. The ability of Treg-reconstitution to protect against GVHD caused by transfer of donor T cells is currently under investigation.