Functional inactivation of pulmonary MAIT cells following 5-OP-RU treatment of non-human primates

Abstract

Targeting MAIT cells holds promise for the treatment of different diseases and infections. We previously showed that treatment of Mycobacterium tuberculosis infected mice with 5-OP-RU, a major antigen for MAIT cells, expands MAIT cells and enhances bacterial control. Here we treated M. tuberculosis infected rhesus macaques with 5-OP-RU intratracheally but found no clinical or microbiological benefit. In fact, after 5-OP-RU treatment MAIT cells did not expand, but rather upregulated PD-1 and lost the ability to produce multiple cytokines, a phenotype resembling T cell exhaustion. Furthermore, we show that vaccination of uninfected macaques with 5-OP-RU+CpG instillation into the lungs also drives MAIT cell dysfunction, and PD-1 blockade during vaccination partly prevents the loss of MAIT cell function without facilitating their expansion. Thus, in rhesus macaques MAIT cells are prone to the loss of effector functions rather than expansion after TCR stimulation in vivo, representing a significant barrier to therapeutically targeting these cells.

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

“…Two readers independently performed image analysis for each animal using consistent lesion labeling determined by a third reviewer. Three-dimensional projections of FDG uptake in the lung regions were generated using Osirix v 5.9 software (Pixmeo, Geneva, Switzerland) as previously described 86 .…”

Augmentation of the Riboflavin-Biosynthetic Pathway Enhances Mucosa-Associated Invariant T (MAIT) Cell Activation and Diminishes Mycobacterium tuberculosis Virulence

“…Moreover, analogous to conventional T cells, MAIT cells have also been found to contribute to the development of immunological memory ( 43 , 80 ). Since MAIT cells are well suited for controlling infection at the pulmonary mucosal surface, fine-tuning of MAIT cell behavior using a suitable vehicle to deliver MR1 ligands to this compartment may constitute a valuable strategy for developing MAIT cell-based vaccines ( 55 , 81 , 82 ).…”

“…As MAIT hi mice do not offer any further control in TB infection in the case of a RibA2 overexpression strain, future studies measuring the changes in MAIT cell numbers and its activation status in vivo in MAIT hi versus MAIT lo mice with these strains could potentially determine if the MAIT hi mice exhibit any further enhancement in MAIT cell number and activity on RibA2 overexpression or if there is a “ceiling” effect in terms of MAIT cell number or activation status with respect to their efficacy against infection. Recent studies highlight the possibility of immune exhaustion and impairment of MAIT cell functions on chronic activation and engagement that may cause these cells to shift from protective to nonprotective functions, for example, in the case of HIV ( 41 ), hepatocellular carcinoma ( 86 ), and 5-OP-RU-based vaccination ( 55 ). Alternatively, there may exist a yet-unidentified MAIT cell-independent protective mechanism in these mice.…”

“…MAIT cells were also found to be activated in response to BCG vaccination in the nonhuman primate model, further suggesting that MAIT cells are subject to modulation by vaccination in a manner similar to conventional T cells ( 54 ). However, compared to M. tuberculosis infection, BCG is a poor inducer of MAIT cell responses ( 54 , 55 ).…”

Design Study of a Novel Positron Emission Tomography System for Plant Imaging

“…Several efforts on plant PET investigations have been made so far using conventional scanners (Ariño-Estrada et al, 2019 ; Ruwanpathirana et al, 2021 ) but with samples positioned vertically inside the camera: the plant displacement along the radial direction of the FOV causes non-uniformity in terms of spatial resolution. However, there are few attempts of PET scanners with the FOV extended in vertical that are conquering a niche in the field of personalized bioimaging (Norvall et al, 2021 ; Sakai et al, 2021 ). That reveals a nice suggestion to move toward the trend of personalized screening approach on plants as well.…”