T-cell derived interferon gamma is required for restriction of Mycobacterium tuberculosis in the murine lung: A reappraisal of conflicting models

Abstract An effective vaccine for Mycobacterium tuberculosis (Mtb) is urgently needed, yet its development has been hampered by incomplete understanding of immunity to Mtb. While vaccine candidates are routinely assessed by their ability to induce CD4+ T cell-derived interferon gamma (IFNγ), this marker has been unreliable in predicting vaccine protection against TB. Furthermore, T cell adoptive transfer studies in RAG1−/− mice have suggested that lung T cell-derived IFNγ only plays a minor role in pulmonary immunity against Mtb. In contrast with prior results, our experiments using IFNγ−/− T cell chimeric mice, and with TCRβ−/− δ−/− mice receiving adoptively transferred IFNγ−/− T cells, demonstrate that control of lung Mtb burden is in fact dependent on T cell-derived IFNγ. We show that this discrepancy is partially due to the confounding effects of RAG−/− vs. the more specific TCRβ−/− δ−/− hosts. Flow cytometry and RNA-seq analysis of lung cells in WT, IFNγ−/−, and TCRβ−/− δ−/− T cell-chimeric mice reveal that absence of T cell-derived IFNγ decreases recruitment of monocyte-derived macrophages to the infected lung, skews infected and bystander macrophages to an alternative M2 phenotype, and promotes neutrophil and eosinophil influx. Together, these results reassert and characterize the role of T cell-derived IFNγ in protection against pulmonary Mtb. Supported by grants from NIH (T32 AI007044, U19 AI135976) and the Firland Foundation (Northrop-Park Fellowship).