A novel means of immunoregulation: CD46 attenuates effector responses of human conventional and unconventional T cells by distinct mechanisms (138.8)

Abstract

Listen

Translate article

Abstract Many studies including human genetics have implicated IL10-producing cells as key in limiting immune pathology during infection and in preventing autoimmunity. Here we show that the complement regulator CD46 regulates IL10 production in an IL2-dependent fashion. More specifically, CD3/CD46-activation of human CD4+ T cells in low IL2 induces strong IFNγ secretion, whereas increasing IL2 induces a ‘switch’ to immunosuppressive Tr1-like cells that are initially IFN-γ+/IL10+, and then IL-10+. We propose that CD46 activation initially promotes antimicrobial Th1 effector responses, while expansion of this response increases local IL2, promoting a CD46-dependent switch to IL10-mediated immunoregulation. The significance of this in vivo is supported by the failure of CD3/CD46-activated CD4+ T cells from rheumatoid arthritis patients to switch to the IL10+ state, producing ≥20-fold more IFNγ than IL10. IL10-switching of CD4+ T cells is mediated by the CYT-1 isoform of the alternatively spliced cytoplasmic tail of CD46. Interestingly, human γδ T cells, whose importance to the early effector phase of immune responses is increasingly apparent, express predominantly the CYT-2 isoform of CD46. Thus, they do not produce IL10 in response to TCR/CD46 co-engagement, but rather significantly decrease their IFNγ and TNFα production. Thus, we propose that CD46 uses distinct molecular mechanisms to regulate unconventional and conventional T cells across the span of the immune response.