The fine-tuning of barrier immunity by myeloid cells

Myeloid cells, including conventional dendritic cells (cDCs) and macrophages, are key responders at epithelial barriers, regulating immunity to microbial pathogens and commensals. Equipped with innate receptors, DCs and macrophages sample and monitor the environment, maintaining homeostasis. Upon detection of danger signals these cells become activated, secrete inflammatory cytokines, and promote T cell activation. How dendritic cells at barrier tissues control the balance between tolerance and immunity is still unclear. Conditional Notch2 deficiency within CD11c-expressing cells (Notch2cKO) impairs the development of ESAM-expressing type 2 dendritic cells (ESAM+cDC2). These cells were previously shown to be critical to respond to infection with the enteropathogenic bacterium C. rodentium.
scRNAseq analysis of DC subsets in Notch2fl/flCD11cCre mice showed profound functional defects across all DC subsets, including the recently characterized cDC2b. We observed an expansion of proinflammatory CD26+CD16/32+Axl+ cDC2b. Further, Notch2cKO spontaneously developed increased IgG2c/IgA antibody titers around eight weeks of age, that remained high over time. Prolonged increases in serum immunoglobulin levels led to immune complex deposition in kidney, that is reminiscent of IgA nephropathy. This early onset of lowgrade inflammation was accompanied by increased intestinal immunopathology and permeability, increased fecal colony-forming unit (CFU) counts and dysbiosis, with colonization of pathogenic species. Co-housing of Notch2cKO with WT mice was sufficient to permanently transfer and establish the pathogenic species and promote increased antibody titers in immune sufficient mice. The pathogenic microbiome led to increased mortality in Notch2cKO mice and increased pathology in co-housed mice upon DSS-induced colitis. This increased pathology resulted from a dysregulation of the ratio between TH17 and Treg.
Collectively, Notch2 deficiency within the myeloid compartment was sufficient to compromise the intestinal barrier, enabling long-term colonization by pathogenic species. The resulting low-grade inflammation led to increased and chronically high antibody titers, which deposited as immune complexes in kidneys, suggesting that a pre-clinical autoimmunity can
be initiated by a mild dysbiosis.