MR1-independent activation of human mucosal-associated invariant T cells by mycobacteria

Sara Suliman, Melissa Murphy, Munyaradzi Musvosvi, Anele Gela, Erin W. Meermeier, Hennie Geldenhuys, Christiaan Hopley, Asma Toefy, Nicole Bilek, Ashley Veldsman, Willem A. Hanekom, John L. Johnson, W. Henry Boom, Gerlinde Obermoser, Huang Huang, Mark Hatherill, David M. Lewinsohn, Elisa Nemes, Thomas J. Scriba

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Tuberculosis (TB) is the leading cause of mortality from a single infectious agent, Mycobacterium tuberculosis. Relevant immune targets of the partially efficacious TB vaccine bacille Calmette-Guérin (BCG) remain poorly defined. Mucosal-associated invariant T (MAIT) cells are MHC-related protein 1 (MR1)-restricted T cells, which are reactive against M. tuberculosis, and underexplored as potential TB vaccine targets. We sought to determine whether BCG vaccination activated mycobacteria-specific MAIT cell responses in humans. We analyzed whole blood samples from M. tuberculosis-infected South African adults who were revaccinated with BCG after a six-month course of isoniazid preventative therapy. In vitro BCG stimulation potently induced IFN-g expression by phenotypic (CD8+CD26+CD161+) MAIT cells, which constituted the majority (75%) of BCG-reactive IFN-g- producing CD8+ T cells. BCG revaccination transiently expanded peripheral blood frequencies of BCG-reactive IFN-g+ MAIT cells, which returned to baseline frequencies a year following vaccination. In another cohort of healthy adults who received BCG at birth, 53% of mycobacteria-reactive-activated CD8 T cells expressed CDR3a TCRs, previously reported as MAIT TCRs, expressing the canonical TRAV1-2-TRAJ33 MAIT TCRa rearrangement. CD26 and CD161 coexpression correlated with TRAV1-2+CD161+ phenotype more accurately in CD8+ than CD42CD82 MAIT cells. Interestingly, BCG-induced IFN-g expression by MAIT cells in vitro was mediated by the innate cytokines IL-12 and IL-18 more than MR1-induced TCR signaling, suggesting TCR-independent activation. Collectively, the data suggest that activation of blood MAIT cells by innate inflammatory cytokines is a major mechanism of responsiveness to vaccination with whole cell vaccines against TB or in vitro stimulation with mycobacteria.

Original languageEnglish (US)
Pages (from-to)2917-2927
Number of pages11
JournalJournal of Immunology
Volume203
Issue number11
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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