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Haematologica ; 95(12): 2134-43, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20713457

ABSTRACT

BACKGROUND: CD4(+) regulatory T cells are a specialized subset of T cells that actively control immune responses. Several experimental protocols have been used to expand natural regulatory T cells and to generate adaptive type 1 regulatory T cells for regulatory T-cell-based therapies. DESIGN AND METHODS: The ability of exogenous recombinant human interleukin-10 to induce alloantigen-specific anergy in T cells was investigated and compared to that of interleukin-10 derived from tolerogenic dendritic cells, in mixed lymphocyte cultures. A detailed characterization of the effector functions of the resulting anergized T cells is reported. RESULTS: Interleukin-10, whether exogenous or derived from tolerogenic dendritic cells, induces a population of alloantigen-specific T cells (interleukin-10-anergized T cells) containing type 1 regulatory T cells, which are anergic and actively suppress alloantigen-specific effector T cells present within the mixed population. Interleukin-10-induced anergy is transforming growth factor-ß independent, and is associated with a decreased frequency of alloantigen-specific cytotoxic T lymphocyte precursors, but interleukin-10-anergized T cells are still responsive to third-party, bacterial, and viral antigens. Tolerogenic dendritic cells are more powerful than exogenous interleukin-10 in generating type 1 regulatory T-cell precursors, and are also effective in the context of HLA-matched donors. CONCLUSIONS: Based on these studies, we have developed an efficient and reproducible in vitro method to generate antigen-specific type 1 regulatory T-cell precursors starting from total peripheral blood cells with minimal cell manipulation and suitable for generating type 1 regulatory T cells for regulatory T-cell-based therapies.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Clonal Anergy/immunology , Isoantigens/immunology , T-Lymphocytes/immunology , Candida albicans/immunology , Cell Proliferation/drug effects , Cells, Cultured , Clonal Anergy/drug effects , Cytomegalovirus/immunology , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Interferon-gamma/metabolism , Interleukin-10/pharmacology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Culture Test, Mixed , Monocytes/immunology , Monocytes/metabolism , Oligonucleotide Array Sequence Analysis , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Tetanus Toxoid/immunology , Transforming Growth Factor beta/pharmacology
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