CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity.
Interleukin-10 (IL-10)-treated dendritic cells (DCs) induce an alloantigen- or peptide-specific anergy in various CD4(+) and CD8(+) T-cell populations. In the present study, we analyzed whether these anergic T cells are able to regulate antigen-specific immunity. Coculture experiments revealed that alloantigen-specific anergic CD4(+) and CD8(+) T cells suppressed proliferation of syngeneic T cells in a dose-dependent manner. The same effect was observed when the hemagglutinin-specific CD4(+) T-cell clone HA1.7 or tyrosinase-specific CD8(+) T cells were cocultured with anergic T cells of the same specificity. Anergic T cells did not induce an antigen-independent bystander inhibition. Suppression was dependent on cell-to-cell contact between anergic and responder T cells, required activation by antigen-loaded DCs, and was not mediated by supernatants of anergic T cells. Furthermore, anergic T cells displayed an increased extracellular and intracellular expression of cytotoxic T-lymphocyte antigen (CTLA)-4 molecules, and blocking of the CTLA-4 pathway restored the T-cell proliferation up to 70%, indicating an important role of the CTLA-4 molecule in the suppressor activity of anergic T cells. Taken together, our experiments demonstrate that anergic T cells induced by IL-10-treated DCs are able to suppress activation and function of T cells in an antigen-specific manner. Induction of anergic T cells might be exploited therapeutically for suppression of cellular immune responses in allergic or autoimmune diseases with identified (auto) antigens.
Steinbrink
Kerstin
K
Department of Dermatology, University of Mainz, Langenbeckstrasse 1, D-551312 Mainz, Germany. steinbrink@hautklinik.klinik.uni-mainz.de
Graulich
Edith
E
Kubsch
Sebastian
S
Knop
Jürgen
J
Enk
Alexander H
AH
D000069594:Abatacept; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology; D007937:Leukapheresis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology; D014442:Monophenol Monooxygenase / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007519:Isoantigens; D016753:Interleukin-10; D000069594:Abatacept; D014442:Monophenol Monooxygenase