Sox8 is essential for M cell maturation to accelerate IgA response at the early stage after weaning in mice

Abstract

Microfold (M) cells residing in the follicle-associated epithelium (FAE) of the gut-associated lymphoid tissue are specialized for antigen uptake to initiate mucosal immune responses. The molecular machinery and biological significance of M cell differentiation, however, remain to be fully elucidated. Here, we demonstrate that Sox8, a member of the SRY-related HMG box transcription factor family, is specifically expressed by M cells in the intestinal epithelium. The expression of Sox8 requires activation of RANKL-RelB signaling. Chromatin immunoprecipitation and luciferase assays revealed that Sox8 directly binds the promoter region of Gp2 to increase Gp2 expression, which is the hallmark of functionally mature M cells. Furthermore, genetic deletion of Sox8 causes a marked decrease in the number of mature M cells, resulting in reduced antigen uptake in Peyer’s patches. Consequently, juvenile Sox8-deficient mice showed attenuated germinal center reactions and antigen-specific IgA responses. These findings indicate that Sox8 plays an essential role in the development of M cells to establish mucosal immune responses.

Osteoprotegerin-dependent M cell self-regulation balances gut infection and immunity

“…To identify OPG-expressing cells in the FAE, we performed whole-mount immunostaining of the FAE using the FAE-sheet ( Fig. 1d) 13,14 . We used three M-cell markers: Tnfaip2, GP2, and Spi-B.…”

“…We previously defined GP2 as a hallmark of M-cell full maturation: Spi-B + GP2 high cells are mature M cells that vigorously take up luminal antigens, whereas Spi-B + GP2 -/low cells are immature M cells with lower capacity to take up luminal antigens 13,14 SIgA is the most abundant class of antibodies found on the mucosal surface; these antibodies play important roles in protection against pathogens and in the regulation of the gut microbial community 38 . We previously reported that the IgA response is gradually enhanced during the development of DSS-induced colitis 39 .…”

“…p50/RelA signaling subsequently upregulates expression of the non-canonical NF-κB molecule, p52/RelB 11 , which transactivates two master transcription factors for M-cell differentiation, namely, Spib and Sox8 (refs. 4,6,12,13 ). Newly generated Spi-B + Sox8 + M cells lack GP2 expression and exhibit an immature phenotype.…”

“…Newly generated Spi-B + Sox8 + M cells lack GP2 expression and exhibit an immature phenotype. These cells terminally differentiate into functionally mature Spi-B + Sox8 + GP2 high M cells during migration from the FAE-associated crypts into the dome region 13,14 . The RANK-RelB-Spi-B/Sox8 axis is responsible for differentiation and functional maturation into GP2 high M cells.…”

Microbial Stimulation Reverses the Age-Related Decline in M Cells in Aged Mice

“…M cells are specialised enterocytes normally present in the follicle associated epithelium (FAE) that overlies mucosal lymphoid tissues, such as the small intestinal Peyer’s patches, and equivalents in the nasopharyngeal tract and lung (Date et al, 2017; Kimura et al, 2014; Kimura et al, 2019b; Mabbott et al, 2013). In the intestines, daughter cells derived from Lgr5+ intestinal stem cells at the intestinal crypt base differentiate into M cells upon RANKL stimulation (de Lau et al, 2012) and expression of the transcription factors Spi-B (Kanaya et al, 2012) and Sox8 (Kimura et al, 2019a). M cells transport antigens from the mucosal surface into lymphoid tissues to immune cells that inhabit a unique pocket structure at their basal side (Kolesnikov et al, 2020; Komban et al, 2019).…”