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

• Published in: Blood Vol. 105; no. 7; pp. 2828 - 2835
• Main Authors: Fischer, Karin, Voelkl, Simon, Heymann, Jana, Przybylski, Grzegorz K, Mondal, Krishna, Laumer, Monika, Kunz-Schughart, Leoni, Schmidt, Christian A, Andreesen, Reinhard, Mackensen, Andreas
• Format: Journal Article
• Language: English
• Published: United States 01.04.2005
• Subjects: Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Apoptosis - immunology; CD3 Complex - metabolism; CD4 Antigens - metabolism; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8 Antigens - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Division - immunology; Flow Cytometry; Humans; Immune Tolerance - immunology; Immunomagnetic Separation; Immunophenotyping; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Thymus Gland - cytology
• ISSN: 0006-4971
• DOI: 10.1182/blood-2004-07-2583

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 naive 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.