Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

Wong, Eileen A.; Joslyn, Louis; Grant, Nicole L.; Klein, Edwin; Lin, Philana Ling; Kirschner, Denise E.; Flynn, JoAnne L.

doi:10.1128/IAI.00426-18

Title: Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

Journal Article · Mon Jun 11 00:00:00 EDT 2018 · Infection and Immunity

DOI:https://doi.org/10.1128/IAI.00426-18· OSTI ID:1544219

Wong, Eileen A. ^[1]; Joslyn, Louis ^[2]; Grant, Nicole L. ^[3]; Klein, Edwin ^[4]; Lin, Philana Ling ^[5]; Kirschner, Denise E. ^[2];

^[1]

Univ. of Pittsburgh, PA (United States), School of Medicine
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
Univ. of Pittsburgh, PA (United States). Dept. of Infectious Disease and Microbiology
Univ. of Pittsburgh, PA (United States). Dept. of Lab. Animal Research
Univ. of Pittsburgh, PA (United States). Dept. of Pediatrics

The hallmarks of pulmonary Mycobacterium tuberculosis infection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells and M. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study of M. tuberculosis infection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs during M. tuberculosis infection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity of M. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

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Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AI123093; HL131072; HL110811; T32AI060525; MCB140228; AC02-05CH11231

OSTI ID:: 1544219

Journal Information:: Infection and Immunity, Vol. 86, Issue 9; ISSN 0019-9567

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 20 works

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