Indoleamine 2-3, dioxygenase in non-hematopoietic cells shapes tuberculous lesion formation and protective immunity 2195

Abstract Description Tuberculosis (TB) lung pathology comes in a range of lesion types including necrotic granulomas defined by a necrotic core, and lesions of alveolitis where lung integrity is intact. Granulomas develop in response to primary Mycobacterium tuberculosis (Mtb) infection, whereas alveolitis is associated with prior Mtb immunity. To investigate the mechanisms of Mtb lesion formation we use a model of concomitant Mtb infection (coMtb) in C3HeB/FeJ mice which form necrotizing granulomas in primary infections and alveolitis with coMtb. Features of coMtb include: 1) an early and robust CD4 T cell response that is necessary and sufficient to prevent necrotizing granulomas and 2) prevention of a dysregulated neutrophil response that drives granuloma necrosis. TB lesions in coMtb are also associated with non-hematopoietic indoleamine 2,3-dioxygenase (IDO-1), a critical enzyme for tryptophan metabolism into immunomodulatory kynurenines. Importantly, we find non-hematopoietic IDO-1 within TB lesions is dependent on CD4-derived IFN-γ, leading to the hypothesis that IFN-γ induces non-hematopoietic IDO-1 which prevents the establishment of a dysregulated neutrophil response and promotes lesions of alveolitis. We determined non-hematopoietic IFN-γ signaling and IDO-1 expression was protective in prior immunity and prevented necrotizing granulomas. These results highlight a context dependent role for IDO-1 in Mtb infection and a novel role for non-hematopoietic cells in TB lesion formation. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)