Migration of marginal zone precursor B cells into the T-cell zone promoted by interferon-alpha induces a T-dependent germinal center response (99.33)

Abstract

Abstract The immunopathogenic mechanisms by which IFNα triggers and promotes autoimmune B-cell responses have not been well characterized. In the spleens of autoimmune BXD2 mice, we found very high numbers of plasmacytoid dendritic cells (pDCs) in the marginal zone (MZ) that produce high levels IFNα. There is a larger population of MZ precursor (MZP) B cells, defined as being IgMhighCD21high and CD23high in BXD2 mice as compared to normal B6 mice. MZP B cells express high levels of ICOS ligand, CD80 and CD86, but low levels of ICOS. MZP B cells are extremely efficient antigen presenting cells (APCs) to induce Ag specific CD4 T cell activation more effectively compared to follicular (FO) and conventional CD23low MZ B cells in the spleens of BXD2 mice. IFNα induced higher levels of CD69 expression by MZP B cells and lead to greater suppression of the S1P induced chemotactic response by MZP B cells as compared to conventional MZ and FO B cells. Knockout of IFNαR in BXD2 mice abrogated the development of the spontaneous autoreactive GCs, and this is associated with significant reduction of IFNα-induced CD69 upregulation in MZP B cells and dramatic suppression of MZP migration into the T-cell zone following toll-like receptor 9 stimulation in vivo. Our results indicate that IFNα− producing pDCs that are localized primarily in the MZ of the spleen can promote a T dependent humoral response through their regulation of the migration of high APC function MZP B cells in the spleens of autoimmune BXD2 mice.