Co-stimulatory molecules decide T cell fate through regulations of their invigoration and impairment

T cell invigoration is an essential step for eliminating pathogens and cancer cells. Co-stimulatory molecules, such as CD80, CD86, and ICOSLG reinforce TCR stimuli for T cell activations. Despite identifying multiple co-stimulatory molecules, the differences of those in downstream signaling have remained unclear. Here, we unravel the differences in avidity of co-stimulatory molecules with T cells cause distinct T cell fates. Specially, CD80 + TCR stimulus promotes induction of multiple T cell effector genes based on prolonged and magnified activation of ERK and AKT compared with other combined stimuli. Long-term and robust activation of these signaling pathways leads to T cell impairment by induction of PD1, and exhausted T cells are vulnerable to disrupt effector functions by interactions with PDL1. Collectively, we reveal the quantitative differences in binding activities of co-stimulatory molecules to T cells cause qualitative differences in downstream signals and gene expressions, thereby branching T cell fates.