The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial–meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells. which may help maintain immune privilege within the CNS.

Author contributions. C.S., P.L.C and S.Z. contributed equally to this work. M. Cella designed, performed and interpreted experiments. R.G. and S.Z. analyzed scRNA-seq data and wrote methods for scRNA-seq analysis. C.S. generated Aiolos-and T-bet-transduced MNK3 cells. M.L.R. and V.P. analyzed the microarray data and RNA-seq data. K.Z. and M.N.A. provided bioinformatic support. J.K.B., K.Y. and V.C. helped in flow cytometry data presentation and analysis. C.F. and R.F. generated libraries for scRNA-seq. J.S. provided critical advice for Cytof analysis. W.G., L.-L.L. and M.B. provided critical insights to the study. S.G., R.A.F. and L.S. provided key reagents. P.L.C. performed cut and run experiment and interpreted data under supervision of E.M.O. S.A.J. and M. Colonna supervised the study. M. Cella, S.A.J. and M. Colonna wrote the manuscript and all the authors contributed editing and suggestions.

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CD4 + effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff actually adopt in frontline tissues in vivo , we applied single-cell transcriptome and chromatin analysis on colonic Teff cells, in germ-free or conventional mice, or after challenge with a range of phenotypically biasing microbes. Subsets were marked by expression of interferon-signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic T H subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as T H markers distributed in a polarized continuum, which was also functionally validated. Clones derived from single progenitors gave rise to both IFN-γ and IL17-producing cells. Most transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activity of AP1 and IRF transcription factor families, not the canonical subset master regulators T-bet, GATA3, RORγ.

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Qian et al. shows that ILC2s can be generated from not only thymic multipotent progenitors but also committed T cell precursors. These processes are greatly suppressed by E protein transcription factors. Thymic ILC2s show functional differences from those made elsewhere.

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Under conventional conditions, mice deficient in core 1-derived O-glycans (TM-IEC C1galt1−/−), which have a defective mucus layer, experienced spontaneous inflammation of the colon. Analysis of fecal bacterial populations by pyrosequencing of 16S rRNA gene showed that disease in conventional TM-IEC C1galt1−/− was associated with shifts in the microbiota manifested by increases in Lactobacillus and Clostridium species, and decreases in unclassified Ruminococcaceae and Lachnospiraceae. Under germ-free (GF) conditions, TM-IEC C1galt1−/− presented decreased goblet cells, but did not develop inflammation. Monoassociation of GF TM-IEC C1galt1−/− revealed that bacterial species differ significantly in their ability to induce inflammatory changes. Bacteroides thetaiotaomicron caused inflammation, while Lactobacillus johnsonii (enriched during colitis) did not. These observations demonstrate that not all microbiota shifts that correlate with disease contribute to pathogenesis.