The Influence of Co-Signaling Proteins on Restimulation-Induced Cell Death in Effector T Lymphocytes

The immune system consists of a tightly self-regulated system that balances appropriate expansion and contraction of cell populations in order to control infections while preventing autoimmunity. One such regulatory mechanism, called restimulation-induced cell death (RICD), is a propriocidal mechanism of apoptosis in which a proportion of activated T cells succumb to death following restimulation through the T cell receptor (TCR) as a means to limit rampant T cell expansion. Mutations in key signaling proteins which mediate RICD sensitivity cause autoimmunity and associated immunopathology, highlighting the significance of RICD in maintaining a healthy immune system. A significant contributing factor for facilitating RICD sensitivity in T cells is the strength of the TCR signal during restimulation: the more intense the signal, the higher proportion of the population will commit to apoptosis. We and others have discovered that proteins that regulate TCR signal strength during restimulation play immediate, critical roles in directing T cell populations towards or away from apoptosis commitment. We hypothesize, therefore, that co-signaling proteins TIM-3 and PD-1 - which directly fine-tune TCR signal strength - are important contributors to RICD sensitivity during the course of expansion and/or contraction of T cells. In this study, we found that both co-signaling proteins influence RICD sensitivity of effector T lymphocytes through distinct mechanisms. PD-1 protects expanding populations (day 4 post-activation) through SHP2 activity and BATF expression, with larger implications for changing the transcriptional landscape to allow them to survive in the face of strong restimulation; its absence in late-stage effectors likely contributes to stronger TCR signal strength through the absence of SHP2 activity and BATF, thereby increasing RICD indirectly during T cell contraction.