ABSTRACT
Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
Subject(s)
Alcohol Drinking/immunology , Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Ethanol/pharmacology , T-Lymphocytes, Helper-Inducer/drug effects , Acetic Acid/metabolism , Acetic Acid/pharmacology , Animals , Arthritis, Experimental/prevention & control , Arthritis, Rheumatoid/prevention & control , Autoantibodies/immunology , Autoimmunity/drug effects , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Collagen/administration & dosage , Collagen/immunology , Ethanol/metabolism , Female , Humans , Mice , Protective Factors , Self Tolerance/drug effects , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
The minimum requirements for in vitro modelling of natural CD4+ T-cell differentiation into T follicular helper (Tfh) cells are still under investigation. We co-cultured wild-type and T-cell receptor (TCR) transgenic CD4+ T cells from naive mice with dendritic cells and B-cell receptor (BCR) transgenic B cells in the presence of HIV-derived virus-like particles containing matched B-cell and T-cell epitopes. This co-culturing induced co-expression of Tfh-master regulator transcription factor BCL-6 and CXCR5 in up to 10% of the wild-type and up to 40% of the TCR-transgenic CD4+ T cells. Phenotypic markers, production of interleukin-21 and isotype switching of the B cells to IgG1 further indicated a helper function of the induced Tfh cells in vitro. Dendritic cells supported the generation of functional Tfh cells, but were unable to induce them without cognate B cells. Hence, our study presents a robust experimental system for efficient generation of functionally active Tfh cells in vitro and confirms the importance of cognate B- and T-cell cross-talk for the Tfh differentiation process.
