Regulatory T cells in γ irradiation-induced immune suppression.
Sublethal total body γ irradiation (TBI) of mammals causes generalized immunosuppression, in part by induction of lymphocyte apoptosis. Here, we provide evidence that a part of this immune suppression may be attributable to dysfunction of immune regulation. We investigated the effects of sublethal TBI on T cell memory responses to gain insight into the potential for loss of vaccine immunity following such exposure. We show that in mice primed to an MHC class I alloantigen, the accelerated graft rejection T memory response is specifically lost several weeks following TBI, whereas identically treated naïve mice at the same time point had completely recovered normal rejection kinetics. Depletion in vivo with anti-CD4 or anti-CD25 showed that the mechanism involved cells consistent with a regulatory T cell (T reg) phenotype. The loss of the T memory response following TBI was associated with a relative increase of CD4+CD25+ Foxp3+ expressing T regs, as compared to the CD8+ T effector cells requisite for skin graft rejection. The radiation-induced T memory suppression was shown to be antigen-specific in that a third party ipsilateral graft rejected with normal kinetics. Remarkably, following the eventual rejection of the first MHC class I disparate skin graft, the suppressive environment was maintained, with markedly prolonged survival of a second identical allograft. These findings have potential importance as regards the immunologic status of T memory responses in victims of ionizing radiation exposure and apoptosis-inducing therapies.
Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland, USA. hugh.mcfarland@fda.hhs.gov
Hugh I
HI
McFarland
Montserrat
M
Puig
Lucja T
LT
Grajkowska
Kazuhide
K
Tsuji
Jay P
JP
Lee
Karen P
KP
Mason
Daniela
D
Verthelyi
Amy S
AS
Rosenberg
D000818:Animals; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002453:Cell Cycle / Q000528:radiation effects; D000939:Epitopes / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics; D005720:Gamma Rays / Q000009:adverse effects*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D008212:Lymphocyte Depletion; D051379:Mice; D008822:Mice, Transgenic; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000528:radiation effects*; D014158:Transcription, Genetic; D014184:Transplantation, Homologous / Q000276:immunology; D014916:Whole-Body Irradiation
D016827:CD8 Antigens; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015395:Histocompatibility Antigens Class I