Humblin et al. reported the central role of CD28 in the long-term maintenance and metabolic fitness of virus-specific precursor exhausted (TCF1+PD-1+) CD8+ T (Tpex) cells during chronic LCMV infection in mice. Continuous low levels of CD28 signaling during persistent antigen stimulation were essential to maintain the mitochondrial fitness and self-renewal of Tpex cells. Stronger CD28 signaling on Tpex cells was needed to engage glycolysis, increase IRF4 expression, and promote Tpex conversion into TCF1neg exhausted Tex cells that retained their effector function, and did not compromise the longevity of the response.
Contributed by Shishir Pant
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.