Activated Peyer′s patch B cells sample antigen directly from M cells in the subepithelial dome

Abstract

The germinal center (GC) reaction in Peyer′s patches (PP) requires continuous access to antigens, but how this is achieved is not known. Here we show that activated antigen-specific CCR6 + CCR1 + GL7 − B cells make close contact with M cells in the subepithelial dome (SED). Using in situ photoactivation analysis of antigen-specific SED B cells, we find migration of cells towards the GC. Following antigen injection into ligated intestinal loops containing PPs, 40% of antigen-specific SED B cells bind antigen within 2 h, whereas unspecifc cells do not, indicating B cell-receptor involvment. Antigen-loading is not observed in M cell-deficient mice, but is unperturbed in mice depleted of classical dendritic cells (DC). Thus, we report a M cell-B cell antigen-specific transporting pathway in PP that is independent of DC. We propose that this antigen transporting pathway has a critical role in gut IgA responses, and should be taken into account when developing mucosal vaccines.

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

“…In the intestines, daughter cells derived from Lgr5+ intestinal stem cells at the intestinal crypt base differentiate into M cells upon receiving stimulation via the cytokine receptor activator of nuclear factor-kB ligand (RANKL) (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). Mice lacking intestinal M cells have delayed development of mucosal antibody (IgA)-secreting plasma cell responses due to impaired Peyer's patch germinal center (GC) formation and T follicular helper (Tfh) cell differentiation and develop more severe pathology when infected with intestinal pathogens such as Citrobacter rodentium (Nakamura et al, 2020).…”

Recent Insights into Cellular Crosstalk in Respiratory and Gastrointestinal Mucosal Immune Systems

“…Recent studies showed that the early IgA response occurs without clonal selection in CCR6 + B cells of the SED. This is in contrast to other LNs, in which B cell clones that exhibit low affinity to Ags fail to survive, and high-affinity Ag receptor-expressing B cell clones are preferentially selected for differentiation into early plasmablasts in GCs ( 81 , 82 ). CCR6 + B cells localized to the SED generally encounter Ags that have been transcytosed by M cells.…”

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

“…Increased antigen trafficking into the Peyer’s patch would stimulate naïve lymphocytes. This could be enhanced by activated antigen-specific B cells that can sample antigens directly from M cells and migrate to the GC (Komban et al, 2019). Additional mechanisms beyond antigen transcytosis could also contribute to increased IgA production and GC reactions in aged mice.…”

“…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). Mice lacking intestinal M cells have delayed development of IgA-secreting plasma cell responses due to impaired germinal centre (GC) formation and T follicular helper (Tfh) cell differentiation (Rios et al, 2016).…”