Bulk RNA sequencing of PD1hi vs PD1low TCF-1+ P14 precursor cells sorted 7 days after infection with LCMV Armstrong [bulk RNA-seq]

T-cell exhaustion limits effector T-cell function in chronic infection and tumors. The development of these hypofunctional T-cells was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found strong diversity among precursor T-cells formed early in acute infections. This includes precursors of normal memory T-cells and cells with phenotypes, gene-expression, and epigenetic profiles that resemble precursors of exhausted T-cells found in chronic infections. We demonstrate that high ligand affinity promotes, and PD-1 signaling restricts the development of these precursors. While these exhausted precursors are initially frequently found, they decline without being completely lost in infections the immune system resolves. We therefore concluded that T-cells are preemptively generated irrespectively of the outcome of the infection.