Allogeneic stimulation of naturally occurring CD4 super(+)CD25 super(+) T cells induces strong regulatory capacity with increased donor-reactivity

Current therapies in transplantation require continuous immunosuppression and do not result in transplantation tolerance. It is increasingly appreciated that CD4 super(+)CD25 super(+) regulatory T-cell (T sub(REG)) activation is pivotal for the induction and maintenance of peripheral tolerance. To o...

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Published in:Transplant immunology 2007-06, Vol.17 (4), p.237-242
Main Authors: Coenen, Jeroen JA, Koenen, Hans JPM, Emmer, Peter M, Van Rijssen, Esther, Hilbrands, Luuk B, Joosten, Irma
Format: Article
Language:English
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Summary:Current therapies in transplantation require continuous immunosuppression and do not result in transplantation tolerance. It is increasingly appreciated that CD4 super(+)CD25 super(+) regulatory T-cell (T sub(REG)) activation is pivotal for the induction and maintenance of peripheral tolerance. To optimally exploit T sub(REG) in allograft tolerance, we investigated how to further harness their function. In vitro, CD4 super(+)CD25 super(+)T cells were expanded by allogeneic bone-marrow derived DC or polyclonal stimulation and were compared in suppressive capacity and phenotype. In vivo, naive allogeneic CD4 super(+)CD25 super(+)T cells were analyzed in wild type hosts for proliferative capacity and suppressive capacity upon priming by alloantigen. DC of donor origin were found to potently stimulate alloreactive T sub(REG) in vitro. This was accompanied by a substantial enhancement of the suppressive capacity of the T sub(REG) population as a whole, likely due to a proportional rise of alloreactive T sub(REG) as indicated by CFSE analysis. In vivo analysis of infused naturally occurring allogeneic T sub(REG) revealed a robust proliferative capacity for T sub(REG) upon stimulation. Moreover, allogeneic skin transplantation resulted in enhanced capacity of the T sub(REG) population to suppress the response towards donor antigens. Combining, activation of alloreactive T sub(REG) is an intrinsic part of the regular alloimmune response and this feature can be exploited for therapeutic purposes. We propose that selectively favoring the effects of alloreactive T sub(REG) is a pivotal element in inducing graft acceptance.
ISSN:0966-3274
DOI:10.1016/j.trim.2007.01.004