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Early regulation of CD8 T cell alloreactivity by CD4+CD25– T cells in recipients of anti‐CD154 antibody and allogeneic BMT is followed by rapid peripheral deletion of donor‐reactive CD8+ T cells, precluding a role for sustained regulation

While acquisition of regulatory function by CD4+CD25– T cells has been reported following antigenic stimulation, “naturally occurring” regulatory CD4+ T cells (Treg) are believed to express CD25. We examined the mechanisms involved in peripheral CD8 T cell tolerance by induction of mixed chimerism using non‐myeloablative conditioning with low‐dose (3 Gy) total body irradiation and anti‐CD154 antibody. Recipient CD4+ T cells were initially required for the induction of CD8 cell tolerance, but were not needed beyond 2 weeks. Depletion of CD25+ Treg prior to bone marrow transplantation and blockade of IL‐2 with neutralizing antibody did not impede tolerance induction. Tolerance was dependent on CTLA4, but not on IFN‐γ. In C57BL/6 mice containing a fraction of 2C TCR transgenic CD8+ T cells, which recognize the MHC class I alloantigen Ld, induction of chimerism with Ld+, but not Ld–, bone marrow cells led to deletion of peripheral 2C+ CD8+ cells within 1 week in peripheral blood and spleen. Complete deletion required the presence of recipient CD4+ T cells. Thus, a novel, rapid form of regulation by CD4+CD25– T cells permits initial CD8 T cell tolerance in this model. Rapid peripheral deletion of donor‐specific CD8 T cells precludes an ongoing requirement for CD4 T cell‐mediated regulation.