Limited Pulmonary Mucosal-Associated Invariant T Cell Accumulation and Activation during Mycobacterium tuberculosis Infection in Rhesus Macaques

Abstract

Mucosal-associated invariant T cells (MAITs) are positioned in airways and may be important in the pulmonary cellular immune response against infection, particularly prior to priming of peptide-specific T cells. Accordingly, there is interest in the possibility that boosting MAITs through tuberculosis (TB) vaccination may enhance protection, but MAIT responses in the lungs during tuberculosis are poorly understood. In this study, we compared pulmonary MAIT and peptide-specific CD4 T cell responses in-infected rhesus macaques using 5-OP-RU-loaded MR-1 tetramers and intracellular cytokine staining of CD4 T cells following restimulation with an -derived epitope megapool (MTB300), respectively. Two of four animals showed a detectable increase in the number of MAIT cells in airways at later time points following infection, but by ∼3 weeks postexposure, MTB300-specific CD4 T cells arrived in the airways and greatly outnumbered MAITs thereafter. In granulomas, MTB300-specific CD4 T cells were ∼20-fold more abundant than MAITs. CD69 expression on MAITs correlated with tissue residency rather than bacterial loads, and the few MAITs found in granulomas poorly expressed granzyme B and Ki67. Thus, MAIT accumulation in the airways is variable and late, and MAITs display little evidence of activation in granulomas during tuberculosis in rhesus macaques.

MAIT cell-directed therapy of Mycobacterium tuberculosis infection

“…Despite previous evidence showing that MAIT cells can respond to Mtb infection, here we find that in mice the endogenous MAIT cell response in the lungs is relatively weak and has no discernible protective role. This is consistent with reports that pulmonary MAIT cells display few markers of activation and do not accumulate in the granulomas of Mtb-infected rhesus macaques 29,30 . However, here we also show that stimulating MAIT cells through their TCR by exogenous administration of 5-OP-RU during chronic infection results in a surprising reduction in bacterial loads.…”

Efficient 5-OP-RU-induced enrichment of Mucosal-associated invariant T cells in the murine lung does not enhance control of aerosolMycobacterium tuberculosisinfection

“…In contrast to these studies, prior literature indicates that MAIT cells undergo limited expansion after pulmonary Mtb infection in mice and macaques (23)(24)(25). This is consistent with our findings: we observed initial MAIT cell depletion from inguinal lymph node, spleen and lung at In BCG vaccinated macaques and humans, MAIT cells demonstrate rapid expansion and enhanced IFNg production (14,34,45).…”

“…As expected during the adaptive response to Mtb infection, pulmonary non-MAIT T cells strongly downregulated the naive L-selectin marker, CD62L. These data are consistent with previous findings (23)(24)(25) demonstrating that MAIT cells respond to acute Mtb challenge, but undergo limited expansion.…”

MAIT cells are minimally responsive to Mycobacterium tuberculosis within granulomas, but are functionally impaired by SIV in a macaque model of SIV and Mtb co-infection

“…While SIV infection alone did not affect MAIT cell function in response to ex vivo mycobacterial stimulus, we did observe an increase in the frequency of MAIT cells expressing ki67 in the blood for both Mtb and SIV/Mtb cohorts (Fig 4), indicating that MAIT cells may be proliferating and responding to an Mtb infection, as observed by others [7,11]. We performed in vitro functional assays using cryopreserved PBMC from the SIV-naïve and SIV+ animals following Mtb infection (Fig.…”