Common genetic variants are associated with risk of lung and autoimmune diseases. However, we have a limited understanding of the pathological effects of these disease variants, specifically in tissue-resident immune cells at the frontier of infection and disease in the lung. To address this, we performed single-cell expression quantitative trait locus (eQTL) analysis across 29 distinct immune cell subsets isolated from lung tissue. Colocalization analysis of lung immune cell eQTLs with genome-wide association study (GWAS) signals from lung diseases, and infectious and autoimmune diseases, implicate disease-associated variants and their target genes functioning in a single or restricted group of cell types. Several genes, including ZFP57, showed significant colocalization between lung immune cell eQTLs and GWAS signals from multiple systemic and organ-restricted autoimmune diseases, highlighting shared genetic mechanisms underlying the risk of disease. Overall, our study shows that disease-associated variants from a wide range of autoimmune diseases impact gene expression in tissue-resident immune cell types (https://lung.dice-database.org).

The mechanisms sustaining chronic inflammation in rheumatoid arthritis (RA) remain incompletely understood. Here we show that branched-chain amino acid (BCAA) catabolism, mediated by the mitochondrial enzyme BCAT2, sustained interferon-driven macrophage activation in autoimmune arthritis. Multi-omics and histological analyses of individuals with active RA or sustained remission revealed that active disease was associated with systemic BCAA depletion, synovial branched-chain ketoacid accumulation and elevated BCAT2 expression in interferon-responsive synovial macrophages. Mechanistically, interferon-γ induced BCAT2 transcription through the transcription factor IRF1 in RA synovial macrophages. In human monocyte-derived macrophages, BCAT2-dependent BCAA catabolism elevated mitochondrial reactive oxygen species, which in turn restrained SHP-1 activity, prolonged STAT1 and STAT2 phosphorylation and drove inflammatory cytokine production. Furthermore, myeloid-specific deletion of Bcat2 ameliorated collagen antibody-induced arthritis in mice. Pharmacological targeting of this pathway with telmisartan suppressed persistent arthritis in methotrexate-treated mice. Together, our findings identified BCAT2-dependent amino acid catabolism as a potentially targetable metabolic pathway in autoimmune arthritis.

Lung tissue-resident memory T (TRM) cells are critical for frontline immunity, yet they undergo rapid attrition in the mouse lung. Whether this paradigm applies to humans has remained unknown. Here we present a comprehensive analysis of T cells from human lungs, characterizing the prevalence and properties of lung TRM cells specific to a broad spectrum of pathogens. Using a T cell receptor-guided approach that integrates single-cell transcriptomics with paired T cell receptor repertoire profiling, we mapped the pathogen specificity of more than 87,000 lung T cells across 40 individuals, the majority of whom harbored TRM cells specific to multiple pathogens. We confirmed that a large fraction of lung TRM clones persist in the lung for many months to years. Thus, in contrast to those of mice, human lungs retain a stable and varied pool of pathogen-specific TRM cells, suggesting that strategies to bolster these responses could provide durable protection against severe lung infections.

Conventional dendritic cells (cDCs) are key sentinels at epithelial barriers, regulating immunity to microbial pathogens and commensals while preserving tissue integrity. NOTCH2 deficiency in CD11c-expressing cells (Notch2[cKO]) disrupts type 2a DC (cDC2a) development, impairs intestinal TH17 immunity and increases susceptibility to enteropathogenic bacteria. This defect leads to persistent dysbiosis in Notch2[cKO] mice, characterized by low-grade inflammation and systemic autoimmune features, including elevated autoantibody titers and renal immune complex deposition. Dysbiosis precedes expansion of highly inflammatory AXL-expressing type 3 DCs (AXL[+]inf-DC3), promoting chronic inflammation and tertiary lymphoid structures driving adaptive immune responses. Notably, dysbiosis is defined by three dominant pathobionts and is transferable to wild-type mice, recapitulating the autoimmune features observed in Notch2[cKO] mice. Here these findings identify a microbiota-DC axis linking intestinal pathobionts to systemic autoimmunity, establishing inflammatory DC3 as the cellular bridge between dysbiosis, chronic inflammation and autoimmune pathogenesis.

Crohn's disease (CD) involves aberrant intestinal T cell immunity and genetic variants associated with disease development. Notably, mutations impairing NOD2 signaling represent the largest genetic risk factor for CD. Paradoxically, although NOD2 variants are associated with CD, its ligand, bacterial muramyl dipeptide, is a potent stimulator of immunity, long recognized as the minimal component required for the adjuvanticity of complete Freund's adjuvant. This paradox highlights a critical gap in our understanding of how NOD2 coordinates the innate-adaptive immune cross-talk required to maintain intestinal homeostasis. Here we show that NOD2 engagement by muramyl dipeptide drives T cell homing to the mesenteric lymph nodes during both homeostasis and infection. This recruitment promotes antigen-specific effector and memory T cell accumulation in the ileal lamina propria, a process essential for effective recall responses and clearance of secondary infection. Mechanistically, this process requires endothelial-intrinsic NOD2 expression, which drives a specialized transcriptional program for leukocyte recruitment.

Eosinophils are now recognized as multifunctional immune cells that contribute to tissue homeostasis, repair, metabolism and host defense in addition to fulfilling their established roles in type 2 immunity and allergic disease. Substantial eosinophil heterogeneity is evident across tissues and inflammatory states, challenging the view that eosinophils are a uniform population of short-lived effector granulocytes. Here we discuss the current understanding of eosinophil development, tissue adaptation and functional specialization across organs and disease contexts. We propose an integrated framework in which eosinophil identity is shaped by four interdependent axes: differentiation and lineage commitment; local environmental cues; time of tissue residence; and inflammatory status. Together, these factors generate eosinophil states that are dynamic, context dependent and continuously tuned to their tissue environment. Viewing eosinophils through this multidimensional lens reframes these cells as adaptable participants in tissue physiology, rather than solely as terminal effectors of type 2 immunity.