Noncanonical 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 Th1 cells and IFNγ, infection produces a spectrum of immunological and pathological phenotypes in diverse human populations. By characterizing Mtb infection in mouse strains that model the genetic heterogeneity of an outbred population, we identified strains that control Mtb comparably to a standard IFNγ-dependent mouse model but with substantially lower lung IFNγ levels. We report that these mice have a significantly altered CD4 T cell profile that specifically lacks the terminal effector Th1 subset and that this phenotype is detectable before infection. These mice still require T cells to control bacterial burden but are less dependent on IFNγ signaling. Instead, noncanonical immune features such as Th17-like CD4 and γδT cells correlate with low bacterial burden. We find the same Th17 transcriptional programs 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.