Cerf-Benssusan, N. | Search bioRxiv

bioRxiv2026

LysoDCs in Peyer's patches program compartmentalized microbiota-specific Th17 responses

Segmented filamentous bacteria (SFB) are a canonical model of microbiota-driven Th17 immunity, but how distinct gut-associated lymphoid tissues shape the quality and effector potential of commensal-specific T-cell responses remains unclear. Here we show that Peyers patches (PPs) and mesenteric lymph nodes (MLNs) generate transcriptionally, clonally, and functionally distinct SFB-reactive CD4 T-cell programs. In PPs, CCR2-dependent monocyte-derived LysoDCs capture luminal SFB and locally prime antigen-specific CD4 T cells. PP priming drives robust T cell activation, Th17 differentiation with type 1 regulatory (Tr1)-like features, preferential clonal expansion within Th17-Tfh17 lineages, and tissue-retention programs. In contrast, CCR2-independent MLN priming induces a less differentiated, recirculating profile dominated by non-expanded clonotypes. Notably, these distinct programs carry functional consequences. Upon transfer into Citrobacter rodentium-infected lymphopenic mice, PP-primed T cells preserve barrier integrity and limit pathology, whereas MLN-primed cells from the same donors fail to provide equivalent protection. Together, these findings establish PP LysoDCs as specialized orchestrators of compartmentalized microbiota-specific immunity and identify the anatomical site of commensal priming as a key determinant of T-cell functional diversification and mucosal immune outcome. HIGHLIGHTSSFB colonization drives compartmentalized effector and regulatory CD4 T-cell programs in PPs versus MLNs. Embigin LysoDCs in PPs directly sample SFB antigens and prime SFB-reactive CD4 T cells locally. PP priming induces Tr1-like Th17 differentiation, preferential Th17-Tfh17 clonal expansion, and tissue residency. PP-primed CD4 T cells ameliorate colitis-associated pathology during enteric infection, whereas MLN-primed cells do not. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/734008v1_ufig1.gif" ALT="Figure 1000"> View larger version (44K): org.highwire.dtl.DTLVardef@8d59dborg.highwire.dtl.DTLVardef@6643borg.highwire.dtl.DTLVardef@19e63a7org.highwire.dtl.DTLVardef@1a0a64b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Myosin-1b interacts with UNC45A and controls intestinal epithelial morphogenesis

Vesicle trafficking and the establishment of apico-basal polarity are essential processes in epithelium morphogenesis. Myosin-1b, an actin-motor able to bind membranes, regulates membrane shaping and vesicle trafficking. Here, we investigate Myosin-1b function in gut morphogenesis and congenital disorders using cell line and zebrafish larvae as well as patient biopsies. In a 3D Caco-2 cyst model, lumen formation is impaired in absence of Myosin-1b. In zebrafish, both Morpholino knock-down and genetic mutation of myo1b result in intestinal bulb epithelium folding defects associated with vesicle accumulation, reminiscent of a villous atrophy phenotype. We show that Myosin-1b interacts with the chaperone UNC45A, genetic deletion of which also results in gut folding defects in zebrafish. Loss of function mutations in UNC45A have been reported in complex hereditary syndromes, notably exhibiting intestinal disorders associated with villous atrophy. In UNC45A-depleted cells and in patient biopsies, Myosin-1b protein level is strikingly decreased. The appearance of Myosin-1b aggregates upon proteasome inhibition in cells points at a degradation mechanism of misfolded Myosin-1b in the absence of its chaperone. In conclusion, Myosin-1b plays an unexpected role in the development of the intestinal epithelium folds or villi downstream UNC45A, establishing its role in the gut defects reported in UNC45A patients. Summary statementMyosin-1b is important for intestinal epithelium folding during zebrafish development and participates in the villous atrophy clinical manifestation downstream UNC45A loss of function.

developmental biology↗