TY - JOUR T1 - Single-cell profiling of tuberculosis lung granulomas reveals functional lymphocyte signatures of bacterial control JF - bioRxiv DO - 10.1101/2020.10.24.352492 SP - 2020.10.24.352492 AU - Hannah P. Gideon AU - Travis K. Hughes AU - Marc H. Wadsworth II AU - Ang Andy Tu AU - Todd M. Gierahn AU - Forrest F. Hopkins AU - Jun-Rong Wei AU - Conner Kummerlowe AU - Nicole L. Grant AU - Kievershen Nargan AU - JiaYao Phuah AU - H. Jacob Borish AU - Pauline Maiello AU - Alexander G. White AU - Sharie Keanne C. Ganchua AU - Amy Myers AU - Cassaundra L. Ameel AU - Catherine T. Cochran AU - Sarah K. Nyquist AU - Joshua M. Peters AU - Jaime A Tomko AU - Lonnie James Frye AU - Jacob M. Rosenberg AU - Angela Shih AU - Michael Chao AU - Charles A. Scanga AU - Jose Ordovas-Montanes AU - Bonnie Berger AU - Joshua T. Mattila AU - Rajhmun Madansein AU - J. Christopher Love AU - Bryan Bryson AU - Philana Ling Lin AU - Alasdair Leslie AU - Samuel M. Behar AU - JoAnne L Flynn AU - Sarah M. Fortune AU - Alex Shalek Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/26/2020.10.24.352492.abstract N2 - In humans and nonhuman primates, Mycobacterium tuberculosis lung infection yields a complex multicellular structure—the tuberculosis granuloma. All granulomas are not equivalent, however, even within the same host: in some, local immune activity promotes bacterial clearance, while in others, it allows persistence or outgrowth. Here, we used single-cell RNA-sequencing to define holistically cellular responses associated with control in cynomolgus macaques. Granulomas that facilitated bacterial killing contained significantly higher proportions of CD4+ and CD8+ T cells expressing hybrid Type1-Type17 immune responses or stem-like features and CD8-enriched T cells with specific cytotoxic functions; failure to control correlated with mast cell, plasma cell and fibroblast abundance. Co-registering these data with serial PET-CT imaging suggests that a degree of early immune control can be achieved through cytotoxic activity, but that more robust restriction only arises after the priming of specific adaptive immune responses, defining new targets for vaccination and treatment.Competing Interest StatementA.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Cogen Therapeutics, Ochre Bio, and Dahlia Biosciences. CL: shareholder and consultant Honeycomb biotechnologies. ER -