Regulatory T cells and organ transplantation.

Sir William Dunn School of Pathology, South Parks Road, Oxford OX13RE, UK.
Seminars in Immunology (Impact Factor: 6.12). 05/2004; 16(2):119-26. DOI: 10.1016/j.smim.2003.12.007
Source: PubMed

ABSTRACT Empirical studies attempting to explain tolerance to transplanted tissues have demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory T-cells mediating transplantion tolerance comprise two sets which can functionally complement each other. The CD4+CD25+ "natural regulator" arises in the thymus, and is preoccupied with self-antigens expressed at sites of inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1-like cells are induced by persistent danger-free antigen in the periphery. The role of these cells is to moderate immune responses to prevent tissue destruction while allowing microbial elimination.

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    ABSTRACT: The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with demethylated Foxp3 and a specific expansion of CD4(+) CD45RA(-) Foxp3(hi) memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid-induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4(+)CD45RA(-) Foxp3(hi) memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance. Copyright © 2015 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 01/2015; DOI:10.1681/ASN.2014050480 · 9.47 Impact Factor

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