T cell differentiation drives programs of resistance to PD-1-mediated inhibition 2260353
Research into basic PD-1 biology, together with the clinical picture of cancer patients treated with PD-1 blockade, converge to emphasize that PD-1 engages complex signaling networks to support T cell homeostasis, differentiation and immune responses. However, there is a lack of comprehensive understanding in the molecular cascades engaged by PD-1 in functionally distinct T cell subpopulations. We use a combination of functional immuno-assays, transcriptional and proteomic profiling of human T cells to demonstrate that effector T cells acquire programs of resistance to PD-1 signaling as they progress through the trajectory from naïve-to-memory differentiation. Overall, PD-1 mediated stronger inhibition via PD-L2 compared to PD-L1. However, we observed differences in the functional responses to PD-1 signaling driven by T cell subset heterogeneity independent of the level of PD-1 expression. In naïve and central memory T cells, PD-1 inhibited cytokine production, cell cycle progression and cellular metabolism. Functional inhibition by PD-1 in these subsets was observed in the presence and absence of CD28 co-stimulation. In contrast, PD-1 ligation led to small inhibition of cytokine production in effector T cells. Critically, the functional, proliferative and metabolic signatures of terminally differentiated effector CD8 T cells were not affected upon stimulation in the presence of PD-1. Integrated transcriptomic and proteomic profiling of highly purified naïve and memory T cells demonstrated that effector T cell differentiation is associated with the development of resistance programs to PD-1-mediated inhibition. Central and effector memory T cells sharing the same T cell receptor and stimulated in the presence of PD-1 confirmed gradual loss of sensitivity to PD-1 signaling in effector T cells. Together, our findings elucidate the cellular and molecular etiologies associated with sensitivity and resistance to PD-1 signaling. The Mathers Foundation, NIH NIGMS Immune Response Regulation: Cellular Mechanisms (IRC)