Complement-bearing immune complexes induce IL-10 and granzyme B production by human CD4+ T cells (88.35)

Abstract

Abstract Induction of complement-induced regulatory T cells (cTregs) occurs through concurrent cross-linking of the TCR and the complement regulatory protein CD46 on naive human CD4+ T cells. The phenotype of cTregs includes the secretion of large amounts of IL-10 as well as production of granzyme B, providing cell-contact independent and cell-contact dependent mechanisms for immunosuppression. Previous work in our lab has demonstrated cTreg induction by both natural and pathogenic ligands for CD46: C3b dimers and the M protein of group A streptococci, respectively. The current studies examine whether a physiological presentation of complement components on immune complexes can stimulate CD46 in a similar fashion. BSA:α-BSA complexes and antibodies to CD3 were used to stimulate human CD4+ T cells. Immune complexes that were opsonized with complement C3b and C4b fragments through treatment with normal human serum induce IL-10 secretion by T cells and production of intracellular granzyme B. Immune complexes that lack opsonizing complement components due to heat-inactivation or EDTA treatment of serum do not induce IL-10 or granzyme B production. As immune responses mature towards many pathogens, immune complexes are formed. We propose that these complexes, when presented to T cells by antigen-presenting cells bearing Fc or complement receptors, generate a regulatory phenotype and thereby quench the immune response. Funding provided by NIH grant AI070489 AADCRC, and the Sandler Program for Asthma Research.