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.

靶向 MAIT 细胞有望治疗不同的疾病和感染。我们之前表明，用 5-OP-RU（一种 MAIT 细胞的主要抗原）治疗结核分枝杆菌感染的小鼠，可扩增 MAIT 细胞并增强细菌控制。我们在这里治疗结核分枝杆菌用 5-OP-RU 气管内感染恒河猴，但没有发现临床或微生物学益处。事实上，在 5-OP-RU 处理后，MAIT 细胞并没有扩增，而是上调了 PD-1 并失去了产生多种细胞因子的能力，这是一种类似于 T 细胞衰竭的表型。此外，我们表明，将 5-OP-RU+CpG 滴入肺部对未感染的猕猴进行疫苗接种也会导致 MAIT 细胞功能障碍，并且在疫苗接种期间阻断 PD-1 可部分防止 MAIT 细胞功能丧失而不促进其扩增。因此，在恒河猴中，体内 TCR 刺激后 MAIT 细胞容易丧失效应功能而不是扩张，这代表了治疗靶向这些细胞的重大障碍。