CD8+ T cells responding to persistent antigenic stimulation, for example during chronic viral infections and cancer, undergo a process named T-cell exhaustion. Exhausted T cells are heterogeneous, consisting of subpopulations with different functional and developmental properties. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that possess long-term proliferative and self-renewal capacities and continuously generate exhausted effector (Tex) cells. However, it is unclear how Tpex cells can sustain T-cell responses to chronic viruses or tumors over long periods of time.

To shed light on this question, scientists at the University of Melbourne and collaborators performed an in-depth metabolic characterization of Tpex cells in chronic lymphocytic choriomeningitis virus (LCMV) infection. Their results showed that Tpex metabolic attributes strongly contrast with those of Tex cells in the same environment.

Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Mechanistically, Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals, Tex lost mTOR signaling capacity. Early transient mTOR inhibition improved long-term T-cell responses and checkpoint inhibition. Transforming growth factor-beta (TGF-beta) repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Thus, Tpex cells preserve their metabolism to retain long-term functionality to sustain T-cell responses during chronic infection. This work also identified the critical role of the TGF-beta-mTOR axis in this process