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 Blood, 1 April 2005, Vol. 105, No. 7, pp. 2828-2835.
Prepublished online as a Blood First Edition Paper on November 30, 2004; DOI 10.1182/blood-2004-07-2583.

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IMMUNOBIOLOGY

Isolation and characterization of human antigen-specific TCR{alpha}{beta}+ CD4-CD8- double-negative regulatory T cells

Karin Fischer, Simon Voelkl, Jana Heymann, Grzegorz K. Przybylski, Krishna Mondal, Monika Laumer, Leoni Kunz-Schughart, Christian A. Schmidt, Reinhard Andreesen, and Andreas Mackensen

From the Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany; Department of Hematology and Oncology, University Medical Center, Ernst-Moritz-Arndt-University, Greifswald, Germany; Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland; and Institute of Pathology, University of Regensburg, Regensburg, Germany.

Down-regulation of immune responses by regulatory T (Treg) cells is an important mechanism involved in the induction of tolerance to allo-antigens (Ags). Recently, a novel subset of Ag-specific T-cell receptor (TCR){alpha}{beta}+ CD4-CD8- (double-negative [DN]) Treg cells has been found to be able to prevent the rejection of skin and heart allografts by specifically inhibiting the function of antigraft-specific CD8+ T cells. Here we demonstrate that peripheral DN Treg cells are present in humans, where they constitute about 1% of total CD3+ T cells, and consist of both naïve and Ag-experienced cells. Similar to murine DN Treg cells, human DN Treg cells are able to acquire peptide–HLA-A2 complexes from antigen-presenting cells by cell contact-dependent mechanisms. Furthermore, such acquired peptide-HLA complexes appear to be functionally active, in that CD8+ T cells specific for the HLA-A2–restricted self-peptide, Melan-A, became sensitive to apoptosis by neighboring DN T cells after acquisition of Melan-A–HLA-A2 complexes and revealed a reduced proliferative response. These results demonstrate for the first time that a sizable population of peripheral DN Treg cells, which are able to suppress Ag-specific T cells, exists in humans. DN Treg cells may serve to limit clonal expansion of allo-Ag–specific T cells after transplantation.


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