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-gamma. 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 L(d+), 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.
Fehr
Thomas
T
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Takeuchi
Yasuo
Y
Kurtz
Josef
J
Wekerle
Thomas
T
Sykes
Megan
M
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D013047:Specific Pathogen-Free Organisms
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand; D007371:Interferon-gamma