Peptidoglycan-linked protein A promotes T celldependent antibody expansion during Staphylococcus aureus infection

A hallmark of Staphylococcus aureus disease in humans is persistent infections without development of protective immune responses. Infected patients generate V_H3 plasmablast expansions and increased V_H3 idiotype Ig; however, the mechanisms for staphylococcal modification of immune responses are not known. We report here that S. aureus-infected mice generate V_H3 antibody expansions via a mechanism requiring MHC-restricted antigen presentation to CD4+ T cells and staphylococcal protein A (SpA), a cell wall-anchored surface molecule that binds Fcγ and V_H3 variant heavy chains of Ig. V_H3 expansion occurred with peptidoglycan-linked SpA from the bacterial envelope but not with recombinant SpA, and optimally required five tandem repeats of its Ig-binding domains. Signaling via receptor-interacting serine/threonine protein kinase 2 (RIPK2) was essential for implementing peptidoglycan-linked SpA superantigen activity. V_H3 clan IgG from S. aureus-infected or SpA-treated animals was not pathogen-specific, suggesting that SpA cross-linking of V_H3 idiotype B-cell receptors and activation via attached peptidoglycan are the determinants of staphylococcal escape from adaptive immune responses.