Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells

Abstract

Antibody-secreting cells (ASCs) lodging in the mucosa of the small intestine are derived from activated B cells that are thought to arise in gut-associated lymphoid tissues (GALT). Upon leaving the GALT, B cells return to the blood where they must express the gut-homing receptors α4β7 and CCR9 in order to emigrate into the small bowel. Recent evidence indicates that gut-associated dendritic cells (DCs) in GALT induce gut-homing receptors on B cells via a mechanism that depends on the vitamin A metabolite retinoic acid (RA). In addition, although ASC associated with other mucosal tissues secrete IgA in an RA-independent fashion, the presence of high levels of RA in intestine and GALT can promote B cell class switching to IgA and, thus, boost the production of IgA in the intestinal mucosa. Here we discuss the role of RA in the imprinting of gut-homing ASC and the evidence linking RA with the generation of intestinal IgA-ASCs.

Requirement for Runx Proteins in IgA Class Switching Acting Downstream of TGF-β1 and Retinoic Acid Signaling

“…Furthermore, we found marked synergistic action of RA and TGF-b1 in IgA CSR. Such synergistic action might occur in vivo, because robust IgA production was observed in mucosal immune tissues, and LP is rich in TGF-b1, and RAproducing DCs exist in LP (5, 10, 11); however, these data cannot support the previous experimental result, in which TGF-b1 inhibited the RA effect on IgA production (9,38). Such a discrepancy comes from differences in the culture conditions used.…”

“…Such a discrepancy comes from differences in the culture conditions used. Mora et al (9,38) used a more complicated system in combination with B cells, DCs, and soluble factors. Thus, the exact signaling molecules affecting the functions of TGF-b1 in RA-treated B cells remain to be identified.…”

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

“…During embryogenesis, maternally derived RA is essential for the development of secondary lymphoid organs (197). In adult mammals, RA controls various immune cells differentiation and thus the ultimate outcome of immune response and host protection (84,137). The dual role of RA promoting tolerance (11,31,139) and immunity (69,70,151) in different disease contexts points to the key notion that RA functions as a regulator of immune response.…”

“…Expression of RALDH is viewed as a key enzyme defining the ability of specific cell types or tissues to produce RA (43,65,144,182). The discovery that RA induces the migration of leukocytes to the gut (84,137,223) has focused much of the attention of RA synthesis to mucosal sites. As such, researchers have begun to elucidate the factors and cells that govern the expression of RALDHs and RA synthesis in immune relevant cells in the gut and in the periphery.…”

Donor single nucleotide polymorphism in the CCR9 gene affects the incidence of skin GVHD

“…22,23 One of their important functions is the selective homing and retention of CCR9-positive T cells and B cells to the small intestine rather than to the colon, which provides a mechanism for regional specialization of the mucosal immune system. 9,24 Another function is regulating intrathymic T-cell development, particularly double-negative to double-positive transition, 25,26 which may be associated with T-cell recovery after allo-HSCT. Therefore, the effect of the CCR9 genotype on acute GVHD is hypothesized to result from its function in the small intestine because T cells educated in the thymus will appear at least 6 months after transplantation.…”