CTLA-4 engagement and regulatory CD4+CD25+ T cells independently control CD8+-mediated responses under costimulation blockade.
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Publication year
2006Source
Journal of Immunology, 176, 9, (2006), pp. 5240-6ISSN
Publication type
Article / Letter to editor
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Organization
Blood Transfusion and Transplantation Immunology
Nephrology
Journal title
Journal of Immunology
Volume
vol. 176
Issue
iss. 9
Page start
p. 5240
Page end
p. 6
Subject
N4i 4: Auto-immunity, transplantation and immunotherapy; NCMLS 2: Immune Regulation; UMCN 1.4: Immunotherapy, gene therapy and transplantation; UMCN 5.4: Renal disordersAbstract
Blockade of costimulatory signals is a promising therapeutic target to prevent allograft rejection. In this study, we sought to characterize to what extent CTLA-4 engagement contributes to the development of transplantation tolerance under the cover of CD40/CD40L and CD28/CD86 blockade. In vitro, we found that inhibition of the primary alloresponse and induction of alloantigen hyporesponsiveness by costimulation blockade was abrogated by anti-CTLA-4 mAb. In addition, regulatory CD4(+)CD25(+) T cells (T(REG)) were confirmed to play a critical role in the induction of hyporesponsiveness by anti-CD40L and anti-CD86 mAb. Our data indicated that CTLA-4 engagement is not required for activation or suppressor function of T(REG). Instead, in the absence of either CTLA-4 signaling or T(REG), CD8(+) T cell division was enhanced, whereas the inhibition of CD4(+) T cell division by costimulation blockade remained largely unaffected. In vivo, the administration of additional anti-CTLA-4 mAb abrogated anti-CD40L- and anti-CD86 mAb-induced cardiac allograft survival. Correspondingly, rejection was accompanied by enhanced allograft infiltration of CD8(+) cells. We conclude that CTLA-4 signaling and T(REG) independently cooperate in the inhibition of CD8(+) T cell expansion under costimulation blockade.
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- Faculty of Medical Sciences [92874]
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