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.
Highlights
Mucosal Associated Invariant T (MAIT) cells are restricted by the nonpolymorphic MHC class I-like molecule MR1 and express TCRs specific for small molecule metabolites produced by microbes.1,2 5-OP-RU, a derivative of intermediates produced during bacterial riboflavin biosynthesis, is a major MR1 ligand that is recognized by a majority of MR1-restricted T cells.[3,4,5] MAIT cells display proinflammatory, cytotoxic, and tissue-repair properties.[6,7,8] Given the non-polymorphic nature of MR1 there is interest in targetingMAIT cells through vaccination or as therapies for the treatment of various conditions including cancer and infections
We previously showed that treating Mycobacterium tuberculosis (Mtb) infected mice with the MAIT cell TCR agonist 5-OP-RU leads to a large expansion of MAIT cells and reduction in lung bacterial loads,[14] prompting us to further evaluate the translatability of MAIT cell directed therapy during TB in the rhesus macaque model
Small effects can be difficult to detect with the groups sizes that can be achieved in aBSL3 non-human primate (NHP) studies, there was no obvious biological effect on MAIT cells to which we could ascribed the lymph node disease in the treated animals
Summary
Mucosal Associated Invariant T (MAIT) cells are restricted by the nonpolymorphic MHC class I-like molecule MR1 and express TCRs specific for small molecule metabolites produced by microbes.1,2 5-OP-RU, a derivative of intermediates produced during bacterial riboflavin biosynthesis, is a major MR1 ligand that is recognized by a majority of MR1-restricted T cells.[3,4,5] MAIT cells display proinflammatory, cytotoxic, and tissue-repair properties.[6,7,8] Given the non-polymorphic nature of MR1 there is interest in targeting. Using mouse models, MAIT cells have been shown to be important for the control of certain bacterial infections,[9,10,11] and they can be driven to expand to large numbers in vivo via vaccination with antigen and adjuvant.[7,12]. Targeting MAIT cells may be useful during Mycobacterium tuberculosis (Mtb) infection.[13] Recently, it was shown that MR1 deficient mice have no defect in bacterial control or survival after Mtb infection,[14,15] and the presence of large populations of MAIT cells at the time of Mtb exposure has no impact on host resistance.[14,15,16] the murine model data indicate that pre-infection vaccination of MAIT cells may not be beneficial for Mtb infection. Received: 24 March 2021 Revised: 28 May 2021 Accepted: 6 June 2021 Published online: 22 June 2021
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