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bioRxiv · 10.64898/2026.06.26.734008

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

Oliveira Correa, R.·Cherrier, M.·Galvani, R. G. A.·Hardy, R.·Robert, A.·Rodari, M. M.·Luciani, C.·Fallet, M.·Jabri, B.·Cerf-Benssusan, N.·Lelouard, H.·Gaboriau-Routhiau, V.
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Abstract

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

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Oliveira Correa, R., Cherrier, M., Galvani, R. G. A., Hardy, R., Robert, A., Rodari, M. M., Luciani, C., Fallet, M., Jabri, B., Cerf-Benssusan, N., Lelouard, H., Gaboriau-Routhiau, V.. 2026-07-01. LysoDCs in Peyer's patches program compartmentalized microbiota-specific Th17 responses. https://doi.org/10.64898/2026.06.26.734008

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