T cell responses against mycobacterial lipids and proteins are poorly correlated in South African adolescents

Chetan Seshadri, Lin Lin, Thomas J. Scriba, Glenna Peterson, David Freidrich, Nicole Frahm, Stephen C. De Rosa, D. Branch Moody, Jacques Prandi, Martine Gilleron, Hassan Mahomed, Wenxin Jiang, Greg Finak, Willem A. Hanekom, Raphael Gottardo, M. Juliana McElrath, Thomas R. Hawn

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Abstract

Human T cells are activated by both peptide and nonpeptide Ags produced by Mycobacterium tuberculosis. T cells recognize cell wall lipids bound to CD1 molecules, but effector functions of CD1-reactive T cells have not been systematically assessed in M. tuberculosis-infected humans. It is also not known how these features correlate with T cell responses to secreted protein Ags. We developed a flow cytometric assay to profile CD1-restricted T cells ex vivo and assessed T cell responses to five cell wall lipid Ags in a cross-sectional study of 19 M. tuberculosis-infected and 22 M. tuberculosis-uninfected South African adolescents. We analyzed six T cell functions using a recently developed computational approach for flow cytometry data in high dimensions. We compared these data with T cell responses to five protein Ags in the same cohort. We show that CD1b-restricted T cells producing antimycobacterial cytokines IFN-g and TNF-α are detectable ex vivo in CD4+, CD8+, and CD42CD82 T cell subsets. Glucose monomycolate was immunodominant among lipid Ags tested, and polyfunctional CD4 T cells specific for this lipid simultaneously expressed CD40L, IFN-g, IL-2, and TNF-α. Lipid-reactive CD4+ T cells were detectable at frequencies of 0.001-0.01%, and this did not differ by M. tuberculosis infection status. Finally, CD4 T cell responses to lipids were poorly correlated with CD4 T cell responses to proteins (Spearman rank correlation 20.01; p = 0.95). These results highlight the functional diversity of CD1- restricted T cells circulating in peripheral blood as well as the complementary nature of T cell responses to mycobacterial lipids and proteins. Our approach enables further population-based studies of lipid-specific T cell responses during natural infection and vaccination.

Original languageEnglish (US)
Pages (from-to)4595-4603
Number of pages9
JournalJournal of Immunology
Volume195
Issue number10
DOIs
StatePublished - Nov 15 2015

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Seshadri, C., Lin, L., Scriba, T. J., Peterson, G., Freidrich, D., Frahm, N., De Rosa, S. C., Moody, D. B., Prandi, J., Gilleron, M., Mahomed, H., Jiang, W., Finak, G., Hanekom, W. A., Gottardo, R., McElrath, M. J., & Hawn, T. R. (2015). T cell responses against mycobacterial lipids and proteins are poorly correlated in South African adolescents. Journal of Immunology, 195(10), 4595-4603. https://doi.org/10.4049/jimmunol.1501285