Regulation of frontline antibody responses by innate immune signals

Abstract

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T-cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T-cell-independent pathway for B-cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly "frontline" B cells located in the marginal zone of the spleen and in the intestine.

Fig. 1

Innate B cell-stimulating signals in the spleen. Canonical neutrophils (N_C cells) colonize peri-MZ areas of the spleen under homeostatic conditions via a non-inflammatory pathway. N_C cells acquire a distinct phenotype and B cell-helper function in response to splenic signals such as IL-10 from sinusoidal endothelial cells and macrophages. The resulting N_BH cells form MZ B cell-interacting NET-like structures to elicit CSR, SHM as well as IgM, IgG, and IgA production via a mechanism involving the cytokines BAFF, APRIL, and IL-21

Fig. 2

Innate B cell-stimulating signals in the intestine. IECs release APRIL and trigger direct IgM-to-IgA1 CSR in LP IgM⁺ B cells and sequential IgA1-to-IgA2 CSR in LP IgA1⁺ B cells after sensing microorganisms through TLRs. iNOS⁺TNF⁺ DCs (TipDCs) and TLR5⁺ DCs cooperate with stromal cells and macrophages to further enhance local IgA CSR and production through a mechanism involving BAFF, APRIL, IL-6, IL-10, and TGF-β1. Similar signals promote the differentiation of IgA class-switched B cells into IgA-secreting plasma cells and facilitate plasma cell survival