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

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 8; pp. 1698 - 1714.e5
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 10.08.2021
• Subjects: checkpoint inhibition; mitochondria; OXPHOS; precursors of exhausted T cells; progenitor T cells; rapamycin; stem-like T cells; T cell exhaustion; T cell function; TCF1; progenitor T cells; T cell function; precursors of exhausted T cells; checkpoint inhibition; mitochondria; T cell exhaustion; OXPHOS; stem-like T cells; TCF1; rapamycin
• ISSN: 1074-7613; 1097-4180
• DOI: 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. [Display omitted] •Tpex cells preserve mitochondrial fitness during chronic infection•TGF-β-mediated mTOR-inhibition preserves metabolism in Tpex cells•TGF-β is a main driver of T cell exhaustion•Early targeting of mTOR signaling promotes long-term T cell responses Exhausted T cells are heterogenous, consisting of subpopulations with different functional and developmental properties. Gabriel et al. demonstrate that TGF-β-mediated mTOR inhibition preserves the cellular metabolism of precursors of exhausted T cells, which both limits and sustains long-term T cell responses in chronic infections.