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

Sakai, Shunsuke; Lora, Nickiana E.; Kauffman, Keith D.; Dorosky, Danielle E.; Oh, Sangmi; Namasivayam, Sivaranjani; Gomez, Felipe; Fleegle, Joel D.; Lindestam Arlehamn, Cecilia S.; Sette, Alessandro; Sher, Alan; Freeman, Gordon J.; Via, Laura E.; Barry, Clifton E.; Barber, Daniel L.

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.