Pre-Germinal Center Interactions with T Cells Are Natural Checkpoints to Limit Autoimmune B Cell Responses

Abstract

Interactions with Ag-specific T cells drive B cell activation and fate choices that ultimately determine the quality of high-affinity Ab responses. As such, these interactions, and especially the long-lived interactions that occur before germinal center formation, may be important checkpoints to regulate undesirable responses. Using mouse model Ag systems, we directly observed interactions between T and B cells responding to the self-antigen myelin oligodendrocyte glycoprotein (MOG) and found that they are of lower quality compared with interactions between cells responding to the model foreign Ag nitrophenyl-haptenated OVA. This was associated with reduced expression of molecules that facilitate these interactions on the B cells, but not on T cells. B cell expression of these molecules was not dictated by the T cell partner, nor could the relative lack of expression on MOG-specific (MOG-sp.) B cells be reversed by a multivalent Ag. Instead, MOG-sp. B cells were inherently less responsive to BCR stimulation than MOG-non-sp. cells. However, the phenotype of MOG-sp. B cells was not consistent with previous descriptions of autoimmune B cells that had been tolerized via regular exposure to systemically expressed self-antigen. This suggests that alternate anergy pathways may exist to limit B cell responses to tissue-restricted self-antigens.