Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 <sup>+</sup> PD-1 <sup>+</sup> CD8 T cells
Étienne Humblin, Isabel Korpas, Jiahua Lu, Dan Filipescu, Verena van der Heide, Simon Goldstein, Abishek Vaidya, Alessandra Soares‐Schanoski, Beatrice Casati, Myvizhi Esai Selvan, Zeynep H. Gümüş, Andreas Wieland, Mauro Corrado, Leona Cohen‐Gould, Emily Bernstein, Dirk Homann, Jerry E. Chipuk, Alice O. Kamphorst
Abstract
During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1–positive (PD-1 + ) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1 neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1 + CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.