Abstract
Co-stimulation regulates Tcell activation, but it remains unclear whether co-stimulatory pathways also control Tcell differentiation. We used mass cytometry to profile Tcells generated in the genetic absence of the negative co-stimulatory molecules CTLA-4 and PD-1. Our data indicate that negative co-stimulation constrains the possible cell states that peripheral Tcells can acquire. CTLA-4 imposes major boundaries on CD4+ Tcell phenotypes, whereas PD-1 subtly limits CD8+ Tcell phenotypes. By computationally reconstructing Tcell differentiation paths, we identified protein expression changes that underlied the abnormal phenotypic expansion and pinpointed when lineage choice events occurred during differentiation. Similar alterations in Tcell phenotypes were observed after anti-CTLA-4 and anti-PD-1 antibody blockade. These findings implicate negative co-stimulation as a key regulator and determinant of Tcell differentiation and suggest that checkpoint blockade might work in part by altering the limits of Tcell phenotypes.
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