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. tube...

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Bibliographic Details
Published in:bioRxiv 2021-01
Main Authors: Sakai, Shunsuke, Lora, Nickiana E, Kauffman, Keith D, Dorosky, Danielle E, Oh, Sangmi, Namasivayam, Sivaranjani, Gomez, Felipe, Fleegle, Joel D, Tuberculosis Imaging Program, Cecilia S Lindestam Arlehamn, Sette, Alessandro, Sher, Alan, Freeman, Gordon J, Via, Laura E, Clifton E Barry 3rd, Barber, Daniel L
Format: Article
Language:English
Subjects:
Cytokines
Immunization
Immunoglobulin M
Immunology
Lymphocytes T
PD-1 protein
PD-L1 protein
Phenotypes
T cell receptors
Tuberculosis
Vaccination
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Summary: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 M. tuberculosis infected macaques. 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. Competing Interest Statement D.L.B. has patents on the PD-1/PD-1 pathway. G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant and GV20. G.J.F. has equity in Nextpoint, Triursus, Xios, iTeos, IgM, GV20, and Geode.
ISSN:2692-8205
DOI:10.1101/2021.01.29.428844