Interleukin-10-mediated regulatory T-cell responses to epitopes on a human red blood cell autoantigen.
Regulatory T cells have been shown to control animal models of immune-mediated pathology by inhibitory cytokine production, but little is known about such cells in human disease. Here we characterize regulatory T-cell responses specific for a human red blood cell autoantigen in patients with warm-type autoimmune hemolytic anemia. Peripheral blood mononuclear cells from patients with autoimmune hemolytic anemia were found either to proliferate and produce interferon-gamma or to secrete the regulatory cytokine interleukin 10 when stimulated in vitro with a major red blood cell autoantigen, the RhD protein. Flow cytometric analysis confirmed that the majority of the responding cells were of the CD4(+) phenotype. Serial results from individual patients demonstrated that this bias toward proliferative or interleukin-10 responses was unstable over time and could reverse in subsequent samples. Epitope mapping studies identified peptides from the sequence of the autoantigen that preferentially induced interleukin-10 production, rather than proliferation, and demonstrated that many contain naturally processed epitopes. Responses to such peptides suppressed T-cell proliferation against the RhD protein, an inhibition that was mediated largely by interleukin 10 and dependent on cytotonic T lymphocyte-associated antigen (CTLA-4) costimulation. Antigenic peptides with the ability to stimulate specific regulatory cells may represent a new class of therapeutic agents for immune-mediated disease.
Hall
Andrew M
AM
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen Foresterhill, Aberdeen, United Kingdom.
Ward
Frank J
FJ
Vickers
Mark A
MA
Stott
Lisa-Marie
LM
Urbaniak
Stanislaw J
SJ
Barker
Robert N
RN
D000069594:Abatacept; D000328:Adult; D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000502:physiology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010449:Peptide Mapping; D012204:Rh-Hr Blood-Group System / Q000737:chemistry / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000939:Epitopes; D018796:Immunoconjugates; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen; D016753:Interleukin-10; D000069594:Abatacept; D007371:Interferon-gamma