| First Author | Villegas-Mendez A | Year | 2020 |
| Journal | J Immunol | Volume | 205 |
| Issue | 6 | Pages | 1608-1619 |
| PubMed ID | 32817333 | Mgi Jnum | J:301511 |
| Mgi Id | MGI:6502423 | Doi | 10.4049/jimmunol.2000450 |
| Citation | Villegas-Mendez A, et al. (2020) Exhausted CD4(+) T Cells during Malaria Exhibit Reduced mTORc1 Activity Correlated with Loss of T-bet Expression. J Immunol 205(6):1608-1619 |
| abstractText | CD4(+) T cell functional inhibition (exhaustion) is a hallmark of malaria and correlates with impaired parasite control and infection chronicity. However, the mechanisms of CD4(+) T cell exhaustion are still poorly understood. In this study, we show that Ag-experienced (Ag-exp) CD4(+) T cell exhaustion during Plasmodium yoelii nonlethal infection occurs alongside the reduction in mammalian target of rapamycin (mTOR) activity and restriction in CD4(+) T cell glycolytic capacity. We demonstrate that the loss of glycolytic metabolism and mTOR activity within the exhausted Ag-expCD4(+) T cell population during infection coincides with reduction in T-bet expression. T-bet was found to directly bind to and control the transcription of various mTOR and metabolism-related genes within effector CD4(+) T cells. Consistent with this, Ag-expTh1 cells exhibited significantly higher and sustained mTOR activity than effector T-bet- (non-Th1) Ag-expT cells throughout the course of malaria. We identified mTOR to be redundant for sustaining T-bet expression in activated Th1 cells, whereas mTOR was necessary but not sufficient for maintaining IFN-gamma production by Th1 cells. Immunotherapy targeting PD-1, CTLA-4, and IL-27 blocked CD4(+) T cell exhaustion during malaria infection and was associated with elevated T-bet expression and a concomitant increased CD4(+) T cell glycolytic metabolism. Collectively, our data suggest that mTOR activity is linked to T-bet in Ag-expCD4(+) T cells but that reduction in mTOR activity may not directly underpin Ag-expTh1 cell loss and exhaustion during malaria infection. These data have implications for therapeutic reactivation of exhausted CD4(+) T cells during malaria infection and other chronic conditions. |
