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

Megan K. Proulx, Christine D. Wiggins, Charlotte J. Reames, Claire Wu, Michael C. Kiritsy, Patricia Grace, Clare M. Smith, Cecelia S. Lindestam Arlehamn, Galit Alter, Douglas A. Lauffenburger, Christopher M. Sassetti

Training Data for the Model: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE267774

Abstract: 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.