T Cell Factor 1-Expressing Memory-like CD8+ T Cells Sustain the Immune Response to Chronic Viral Infections

Abstract

Chronic infections promote the terminal differentiation (or "exhaustion") of Tcells and are thought topreclude the formation of memory Tcells. In contrast, we discovered a small subpopulation of virus-specific CD8(+) Tcells that sustained the Tcell response during chronic infections. These cells were defined by, and depended on, the expression of the transcription factor Tcf1. Transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked an effector signature. Unlike conventional memory cells, Tcf1-expressing Tcells displayed hallmarks of an "exhausted" phenotype, including the expression of inhibitory receptors such as PD-1 and Lag-3. This population was crucial for the Tcell expansion that occurred in response to inhibitory receptor blockade during chronic infection. These findings identify a memory-like Tcell population that sustains Tcell responses and is a prime target for therapeutic interventions to improve the immune response in chronic infections.