Donor-reactive CD8 memory T cells infiltrate cardiac allografts within 24-h posttransplant in naive recipients.
Normal immune responses stimulated by pathogenic and environmental antigens generate memory T cells that react with donor antigens and no currently used immunosuppressive drug completely inhibits memory T-cell function. While donor-reactive memory T cells clearly compromise graft outcomes, mechanisms utilized by memory T cells to promote rejection are largely unknown. In this study, we investigated how early endogenous memory cells infiltrate and express effector function in cardiac allografts. Endogenous CD8 memory T cells in nonsensitized recipients distinguish syngeneic versus allogeneic cardiac allografts within 24 h of reperfusion. CD8-dependent production of IFN-gamma and CXCL9/Mig was observed 24 to 72 h posttransplant in allografts but not isografts. CXCL9 was produced by donor cells in response to IFN-gamma made by recipient CD8 T cells reactive to donor class I major histocompatibility complex (MHC) molecules. Activated CD8 T cells were detected in allografts at least 3 days before donor-specific effector T cells producing IFN-gamma were detected in the recipient spleen. Early inflammation mediated by donor-reactive CD8 memory T cells greatly enhanced primed effector T-cell infiltration into allografts. These results suggest that strategies for optimal inhibition of alloimmunity should include neutralization of infiltrating CD8 memory T cells within a very narrow window after transplantation.
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. ads23@case.edu
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AD
Schenk
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T
Nozaki
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M
Rabant
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A
Valujskikh
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Fairchild
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D054370:Chemokine CXCL9 / Q000378:metabolism*; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma