부산대학교 도서관

T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted [CD8.sup.+] T cells are maintained by self-renewing stem-like T cells that provide differentiated [TIM3.sup.+] cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem- like T cells toward [TIM3.sup.+] cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased [TIM3.sup.+] cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell- intrinsic mTOR signal was vital for differentiation of stem-like T cells into the [TIM3.sup.+] state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional [TIM3.sup.+] cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.
Introduction T cell exhaustion is a state of T cell dysfunction; it is characterized by poor effector function, impaired proliferative capacity, and expression of multiple inhibitory receptors, most notably programmed [...]