Resident Memory B Cells in Barrier Tissues

Abstract

Epithelial barriers, which include the gastrointestinal, respiratory, and genitourinary mucosa, compose the body's front line of defense. Since barrier tissues are persistently exposed to microbial challenges, a rapid response that can deal with diverse invading pathogens is crucial. Because B cells have been perceived as indirectly contributing to immune responses through antibody production, B cells functioning in the peripheral organs have been outside the scope of researchers. However, recent evidence supports the existence of tissue-resident memory B cells (BRMs) in the lungs. This population's defensive response was stronger and faster than that of their circulating counterparts and could resist heterogeneous strains. With such traits, BRMs could be a promising target for vaccine design, but much about them remains to be revealed, including their locations, origin, specific markers, and the mechanisms of their establishment and maintenance. There is evidence for resident B cells in organs other than the lungs, suggesting that B cells are directly involved in the immune reactions of multiple non-lymphoid organs. This review summarizes the history of the discovery of BRMs and discusses important unresolved questions. Unique characteristics of humoral immunity that play an important role in the peripheral organs will be described briefly. Future research on B cells residing in non-lymphoid organs will provide new insights to help solve major problems regarding human health.

Keywords: barrier tissues; humoral immunity; mucosal immunity; resident memory B cells; respiratory infection; vaccine.

Figure 1

Overview of lung BRM. BRMs are established in sites exposed to local antigens. It is likely that early lung BRMs derive from the draining LNs and late cross-reactive BRMs originate from lung GC reactions, which occur in iBALTs. Lung BRMs can be located within the iBALTs or reside throughout the lung parenchyma in close contact with alveoli, independent of iBALTs. Upon secondary infection, alveolar BRMs migrate to the inflammation foci, which is mediated by alveolar macrophages, and differentiate into PCs. The corresponding functional role of BRMs in iBALT has not been reported. The illustration of the BRM shows most of the surface molecules described in published studies so far. The upregulation of CD69, which reduces surface expression of S1PR1, is consistently reported. Klf2 is a transcription factor that mediates S1PR1 expression. The expression of genes encoding the LN homing molecules Sell and Ccr7 is downregulated. CXCR3 and CCR6 facilitate recruitment and/or retention of BRM in the lung. In addition, CCR6 is related to BRM differentiation into PCs in recall response. The upregulation of CD44 and CD11a in BRM is also reported. These may serve as an adhesion molecule for BRMs, but their functional role needs to be validated. Compared with circulating MBCs, lung BRMs have been shown to express higher levels of FCRL5, CD80, and PD-L2.

Figure 2

Overview of B cells in multiple peripheral organs. (A) The gut microbiota is a consistent stimulus to immune cells in the gut. MBCs and PCs that are formed access the circulation and return to the gut; this migration is mediated by the chemokine receptors CCR9 and CCR10, and integrin α4β7. PCs reside in the lamina propria and MBCs enter the GC reaction, which results in the evolution of BCR repertoires. (B) Several clues for the existence of skin-associated B cells are provided. B cells that migrate to the skin have higher expression of MHCII, CD1, CD86, CD80, and IgM. The migration to the organ is mediated by CCR6 and CLA. B cells in the skin produce antibodies locally and regulate the immune reaction directly by producing the pro-inflammatory cytokines such as IL-6 or the anti-inflammatory cytokine, IL-10. (C) BRMs are not established in the lower FRT. Upon secondary infection, circulating MBCs rapidly migrate to the tissues in a CXCR3-dependent manner. These cells show higher expression of MBC markers including PD-L2 and CD80. These cells could not stay long in the lower FRT tissues.