mTOR Signaling, Tregs and Immune Modulation

Abstract

Foxp3+ Tregs are central regulators of immune tolerance. As dysregulated Treg responses contribute to disease pathogenesis, novel approaches to target the immunomodulatory functions of Tregs are currently under investigation. mTORC1 and mTORC2 are therapeutic targets of interest. Recent studies revealed that mTOR signaling impacts conventional T-cell homeostasis, activation and differentiation. Moreover, mTOR controls the differentiation and functions of Tregs, suggesting that its activity could be targeted to modulate Treg responses. Here, we summarize how Tregs suppress immune responses, their roles in disease development and methods used to alter their functions therapeutically. We also discuss the diverse effects exerted by mTOR inhibition on the development, homeostasis, and functions of conventional T cells and Tregs. We conclude with a discussion of how modulation of mTOR activity in Tregs may be therapeutically beneficial or detrimental in different disease settings.

Are Regulatory T Cells Defective in Type 1 Diabetes and Can We Fix Them?

“…IL-2/anti-IL-2 Ab complexes have also been used to preferentially promote T reg expansion (40). Modulation of mTOR activity with rapamycin has been shown to promote T reg expansion, survival and function (41). Although no difference in T reg number, proliferation or cytokine production was seen with rapamycin therapy prior to islet transplantation, T regs do have increased suppressive capabilities (42).…”

Role of mTOR Signaling in Tumor Microenvironment: An Overview

“…The mTOR and dual PI3K/mTOR inhibitors have been shown to induce Tregs’ expansion and their immunosuppressive activity, thus correlating with a poor prognosis in cancer patients [123]. Encouragingly, Huijts and her group showed that the PI3K inhibition alone allows for the expansion of Tregs, but without affecting their overall suppressive activity [124].…”

СHANGES OF Glut1, mTOR AND AMPK1α GENE EXPRESSION IN PANCREATIC LYMPH NODE LYMPHOCYTES OF RATS WITH EXPERIMENTAL DIABETES MELLITUS

“…В составе этих комплексов mTOR является «проводником» как внутриклеточных, так и внеклеточных сигна-лов и служит одним из центральных регуляторов метаболизма, роста, пролиферации и выживания лимфоцитов и других клеток [22], а одним из ее блокаторов является метформин, который дей-ствует через АMPK (AMP-activated protein kinase) [7,13]. Высокая активность mTOR способна уси-ливать прогрессию диабета через активацию эф-фекторных провоспалительных субпопуляций лимфоцитов [26,15], и наоборот, низкая спо-собствует дифференцировке Treg [4,34], блоки-рующих инсулит. Поэтому целью работы было выяснить уровень экспрессии мРНК генов Glut1, mTOR и AMPK1α, а также распределение mTOR + лимфоцитов в ПЛУ крыс с экспериментальным стрептозотоцин-индуцированным сахарным ди-абетом (ЭСИСД) и после введений метформина.…”