Comparable Non-canonical T cell responses are associated with protection from tuberculosis in mice and humans

While control of Mycobacterium tuberculosis (Mtb) infection is generally understood to require a Th1-immune response and IFN secretion, infection produces a spectrum of immunological and pathological phenotypes in diverse human populations. By characterizing Mtb infection in a collection of mouse strains that models the genetic heterogeneity of an outbred population, we identified a subset of strains that control Mtb burden comparably to a standard IFN-dependent mouse model but with substantially lower lung IFN levels. Here we report that these mice have significantly fewer Th1 and more Th17 and regulatory T cells and that this phenotype is detectable before infection, indicating a general alteration in immune tone. The CD4 T cells are less activated, have a lower polyfunctionality score, and are specifically lacking the terminal effector Th1 subset. These mice still require T cells to control bacterial burden but are less dependent on IFN signaling for this function. Instead, non-canonical immune features such as CD4 Th17 and T cells correlate with low bacterial burden. We find that the same Th17 transcriptional programs in CD4 T cells are associated with resistance to Mtb infection in humans, implicating specific non-Th1 T cell responses as a common feature of Mtb control across species.