Gabriel et al. investigated effects of TGFβ on metabolism of self-renewing, Ag-specific precursors of exhausted CD8+ T cells (Tpex) and their exhausted progeny (Tex) in chronic viral infection. Enforced TGFβ signaling early in infection inhibited mTOR activity, preserving sustained metabolism of Tpex cells with good mitochondrial fitness and OXPHOS throughout chronic infection. This was accompanied by a large increase in the most terminally exhausted Tex subset, suggesting that TGFβ is a main driver of T cell exhaustion. Inhibiting mTOR signaling early (day 0-4), but not late (day 13-20), promoted a potent, long-lasting T cell response.
Contributed by Katherine Turner
ABSTRACT: 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.