Pediatric patients with constitutively active mutations in the cytosolic double-stranded-DNA-sensing adaptor STING develop an autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients have elevated interferon-stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus-associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M [VM]) that recapitulate human disease also develop lymphocyte-rich BALT. Ablation of either T or B lymphocytes prolongs the survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFNγ, and IFNγR deficiency prolonged the survival of SAVI mice; however, T-cell-dependent recruitment of infiltrating myeloid cells to the lung was IFNγ independent. Lethally irradiated VM recipients fully reconstituted with wild type bone-marrow-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells that express STING. Transcriptional analysis of VM endothelial cells revealed up-regulation of chemokines, proinflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders.

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β7 integrin, a cell adhesion molecule, is present in the form of α4β7 integrin or αEβ7 integrin. α4β7 integrin is expressed on most leucocytes and is essential for their migration to gut-associated lymphoid tissues by interacting with its primary ligand, MAdCAM-1, which is preferentially expressed in gut-associated lymphoid tissues. Although the importance of α4β7 integrin in intestinal inflammation has been established, its role in cutaneous inflammation remains to be elucidated. Here we show that β7 integrin-deficient mice, not αE integrin-deficient mice, are defective in contact hypersensitivity (CHS) responses. β7 integrin deficiency does not affect irritant contact dermatitis. The distribution, migration, and function of antigen presenting cells from β7 integrin-deficient mice are comparable to those from wild-type mice. Moreover, sensitized β7 integrin-deficient T cells are able to respond to antigen stimuli in vitro, and elicit CHS responses when directly injected into the skin. However, they are defective in reaching the skin under inflammatory conditions, resulting in reduced CHS responses when intravenously injected. Furthermore, T cells treated with anti-α4β7 integrin neutralizing antibody elicit impaired CHS responses. These results indicate a novel role of α4β7 integrin in regulating T cell migration to inflammatory skin.

B cells with potent IL-10-dependent regulatory functions (B10 cells) expand in mice and humans during inflammation and autoimmunity. In this study, the fate of B10 cells following in vivo expansion was examined using two distinct il-10 reporter strains: Tiger mice that express cytoplasmic GFP and 10BiT mice that express cell surface Thy1.1. B10 cells from Tiger mice express cytoplasmic IL-10 and GFP with similar kinetics following stimulation in vitro and in vivo. By contrast, B10 cell Thy1.1 expression in 10BiT mice was delayed relative to IL-10 production and persisted even after B10 cells had lost the capacity to produce IL-10. Thy1.1 also served as a marker for B10 cells that expressed plasma cell-associated transcription factors and had the capacity to differentiate into CD138+B220LO antibody-secreting plasma cells in vivo and in vitro. Antibodies secreted by B10 cells included broadly reactive “natural antibodies” and autoantibodies, and were antigen-specific in immunized mice. At the molecular level, B10 cells predominantly expressed a germline-encoded IgM antibody repertoire with diverse VH and VL gene utilization. These results indicate that B10 cells can differentiate following IL-10 secretion to produce broadly-reactive germline-encoded antibodies that may function to rapidly clear antigens and further reduce inflammation and immunopathology.

Non-Hodgkin’s lymphoma is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (Rituximab) is widely used to treat Non-Hodgkin’s lymphoma, even though the initial effectiveness of Rituximab varies widely amongst patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well-established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The collection of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, nor serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma galectin-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated galectin-1 compared with non-malignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy.