Cutting Edge: Allogeneic CD4+CD25+Foxp3+ T Regulatory Cells Suppress Autoimmunity while Establishing Transplantation Tolerance

TLDR

The specificity and suppressive activity of allogeneic T regulatory cells toward self‑reactive T cells remains an unresolved question. This study aimed to determine whether allogeneic Treg cells can suppress self‑reactive T cells. The authors used IL‑2Rβ‑deficient mice, which develop rapid lethal autoimmunity due to impaired Treg production, to test this hypothesis. Adoptive transfer of MHC‑mismatched Treg cells into IL‑2Rβ‑deficient mice engrafted lifelong, skewed toward alloantigens, suppressed autoimmunity, and conferred durable tolerance to skin grafts sharing donor MHC, demonstrating that allogeneic Treg engraftment can control autoimmunity and enable long‑term allograft acceptance.

Abstract

An important unresolved question with regard to T regulatory (Treg) cell specificity and suppressive activity is whether allogeneic Treg cells inhibit self-reactive T cells. In the present study, this issue was addressed using IL-2Rbeta-deficient mice that develop rapid lethal autoimmunity due to impaired production of Treg cells. We show that adoptive transfer of completely MHC-mismatched Treg cells into IL-2Rbeta(-/-) mice resulted in life-long engraftment of the donor cells, which exhibited skewed reactivity toward host alloantigens, and prevented autoimmunity. Thus, Treg cells that underwent thymic selection by peptide/MHC class II complexes distinct from those recognized by autoreactive T cells, still effectively suppress autoimmunity. Remarkably, when such animals were skin grafted, they exhibited dominant tolerance to those grafts bearing MHC molecules that were shared with donor Treg cells. Collectively, these data demonstrate that effective engraftment by allogeneic Treg cells controls autoimmunity and results in permissive conditions for long-term acceptance of allografts.