The self-antigen, thyroglobulin, induces antigen-experienced CD4+ T cells from healthy donors to proliferate and promote production of the regulatory cytokine, interleukin-10, by monocytes.
Thyroglobulin (TG), as autoantigen, induces in vitro proliferation of T and B cells from normal individuals, but the cytokine production differs from that in patients with autoimmune thyroid disease. Here, we investigate whether normal T cells responding to TG are naive, or have previously encountered TG in vivo, using their responses to classic primary and secondary antigens, keyhole limpet haemocyanin (KLH) and tetanus toxoid (TT), respectively, for comparison. While TG elicited T-cell proliferation kinetics typical of a secondary response, the cytokine profile was distinct from that for TT. Whereas TT induced pro-inflammatory cytokines [interleukin-2 (IL-2)/interferon-gamma (IFN-gamma)/IL-4/IL-5], TG evoked persistent release of the regulatory IL-10. Some donors, however, also responded with late IFN-gamma production, suggesting that the regulation by IL-10 could be overridden. Although monocytes were prime producers of IL-10 in the early TG response, a few IL-10-secreting CD4(+) T cells, primarily with CD45RO(+) memory phenotype, were also detected. Furthermore, T-cell depletion from the mononuclear cell preparation abrogated monocyte IL-10 production. Our findings indicate active peripheral tolerance towards TG in the normal population, with aberrant balance between pro- and anti-inflammatory cytokine responses for some donors. This observation has implications for autoantigen recognition in general, and provides a basis for investigating the dichotomy between physiological and pathological modes of auto-recognition.
Nielsen
Claus H
CH
Department of Rheumatology, Institute for Inflammation Research, Copenhagen University Hospital, Copenhagen, Denmark.
Galdiers
Marcel P
MP
Hedegaard
Chris J
CJ
Leslie
R Graham Q
RG
D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013745:Tetanus Toxoid / Q000276:immunology; D013954:Thyroglobulin / Q000276:immunology*
D001324:Autoantigens; D018836:Inflammation Mediators; D013745:Tetanus Toxoid; D016753:Interleukin-10; D007371:Interferon-gamma; D013954:Thyroglobulin; D006433:Hemocyanins; D017493:Leukocyte Common Antigens; C032808:keyhole-limpet hemocyanin