Multimodal profiling of 500K memory T cells identifies a reduction in a polyfunctional Th17-like state associated with tuberculosis progression

Aparna Nathan1–5, Jessica I. Beynor1–5, Yuriy Baglaenko1–5, Sara Suliman2, Kazuyoshi Ishigaki1–5, Samira Asgari1–5, Chuan-Chin Huang6,7, Yang Luo1–5, Zibiao Zhang6,7, Kattya Lopez Tamara2,8, Judith Jimenez8, Roger I. Calderón8, Leonid Lecca8, Ildiko van Rhijn2,9, D. Branch Moody2, Megan B. Murray6,7, Soumya Raychaudhuri1–5,10

1 Center for Data Sciences, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
2 Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
3 Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
4 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5 Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
6 Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
7 Division of Global Health Equity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
8 Socios En Salud, Lima 15001, Peru.
9 Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
10 Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.

Memory T cells have been implicated in the progression of Mycobacterium tuberculosis (M.tb) infection to active tuberculosis (TB) disease, which occurs in a minority of infected individuals. However, specific cell states have not yet been delineated because of limitations of traditional T cell profiling strategies that rely on single classes of markers (e.g., mRNA or protein). By measuring multiple modalities of markers, we can more precisely identify cell states associated with variable progression outcomes. We used a multimodal strategy to characterize the landscape of human memory T cells by computationally integrating high-dimensional mRNA and surface protein expression from single cells. By profiling 500,089 memory T cells from 259 individuals in a Peruvian TB disease progression cohort at immune steady state (i.e., outside of active infection), we defined 31 memory T cell states, including a polyfunctional Th17-like effector memory state that was significantly reduced in individuals who had developed active TB (OR = 0.80, p = 1.21 x 10-6). With ex vivo stimulation, this population was enriched for IL-17 and IL-22 production, but with more capacity to produce IFNγ than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. By deconvoluting this cell state from public data, we demonstrated that its depletion precedes and persists beyond active disease. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.

Aparna Nathan BS

Harvard University

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