Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection.

2021-08-10

Gabriel, Sarah S

Tsui, Carlson

Chisanga, David

Weber, Flora

Llano-León, Manuela

Gubser, Patrick M

Bartholin, Laurent

Souza-Fonseca-Guimaraes, Fernando

Huntington, Nicholas D

Shi, Wei

Utzschneider, Daniel T

Kallies, Axel

OXPHOS

T cell exhaustion

T cell function

TCF1

checkpoint inhibition

mitochondria

precursors of exhausted T cells

progenitor T cells

rapamycin

stem-like T cells

Journal Article

10.1016/j.immuni.2021.06.007

Antigen-specific CD8+ T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-β repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.

link

Immunity 2021; 54(8): 1698-1714.e5

Immunity