Latent Mycobacterium tuberculosis Infection Is Associated With a Higher Frequency of Mucosal-Associated Invariant T and Invariant Natural Killer T Cells

Abstract

Increasing drug resistance and the lack of an effective vaccine are the main factors contributing to Mycobacterium tuberculosis (Mtb) being a major cause of death globally. Despite intensive research efforts, it is not well understood why some individuals control Mtb infection and some others develop active disease. HIV-1 infection is associated with an increased incidence of active tuberculosis, even in virally suppressed individuals. Mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells are innate T cells that can recognize Mtb-infected cells. Contradicting results regarding the frequency of MAIT cells in latent Mtb infection have been reported. In this confirmatory study, we investigated the frequency, phenotype, and IFNγ production of MAIT and iNKT cells in subjects with latent or active Mtb infection. We found that the frequency of both cell types was increased in subjects with latent Mtb infection compared with uninfected individuals or subjects with active infection. We found no change in the expression of HLA-DR, PD-1, and CCR6, as well as the production of IFNγ by MAIT and iNKT cells, among subjects with latent Mtb infection or uninfected controls. The proportion of CD4− CD8+ MAIT cells in individuals with latent Mtb infection was, however, increased. HIV-1 infection was associated with a loss of MAIT and iNKT cells, and the residual cells had elevated expression of the exhaustion marker PD-1. Altogether, the results suggest a role for MAIT and iNKT cells in immunity against Mtb and show a deleterious impact of HIV-1 infection on those cells.

Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection

“…Our study did not reveal differences in iNKT subset abundance or activation phenotype between contacts and controls in this study population, contrasting with recent findings of increased frequency of iNKT cells in latently infected individuals compared with uninfected controls (42). These data suggest that peripheral blood iNKT cells may not be a marker of early TB exposure or initial infection in these cohorts.…”

“…Although peripheral blood MAIT cell depletion at baseline in active pulmonary TB cases has previously been reported (37-39), we detected no significant difference in total or CD8 + MAIT cell baseline abundance in TB contacts. In contrast to a recent report, we did not detect enrichment of CD8 + MAIT cells in latently infected subjects (42). In contrast to the CD8 + MAIT cell subset, CD4 + MAIT cells were relatively enriched within the MAIT cell subset in IGRA + contacts, both at baseline and after MR1 ligand stimulation.…”

“…However, there is little human evidence examining this hypothesized role during the innate immune response to initial Mtb infection, as most studies were performed in cases of reactivation TB (37)(38)(39). Recently, both MAIT and iNKT cells were found to be more abundant in latent TB cases compared with uninfected controls (42). Another study reported decreased IL-17 + CD8 + MAIT cells in persistently IFNγ release assay-negative (IGRA -) healthy household contacts compared with IGRA converters, suggesting that CD8 + MAIT cells may be protective against initial infection (40).…”

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

“…iNKT cells and MAIT cells may contribute to protection from M.tb based on data derived from in vitro and in vivo models of TB. Patients with active TB have reduced levels of iNKT and MAIT cells in peripheral blood or bronchoalveolar lavage samples when compared to healthy donors and individuals with latent TB, suggesting that these cells home to the lung to mediate a protective immune response (84)(85)(86)(87). In a murine model, pulmonary mycobacterial infection leads to recruitment of MAIT cells in the lung, and this was associated with reduced bacterial burden during infection (88).…”

PD‐1‐expressing MAIT cells from patients with tuberculosis exhibit elevated production of CXCL13

“…5,[15][16][17][18] Individuals with latent TB infection have higher frequency of MAIT cells and iNKT cells than patients with active TB. 19 Most of the previous studies rely on MAIT cells from peripheral blood; however, functional role of MAIT cells at local sites of TB infection is still largely unknown.…”