Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage

Abstract

An early memory CD8+ T cell precursor with distinct genome maintenance capacity depends on inhibitory receptor signaling. Potent memory T cell precursors Generation of memory T cells is an essential part of protective immunity against pathogens after initial infection or vaccination. Johnnidis et al. identified a subset of self-renewing early memory CD8+ T cell precursors in mice characterized by expression of CD62L and TCF-1 that emerge after viral infection. During lymphocytic choriomeningitis virus infection, this relatively small subset displayed restrained effector differentiation, genome maintenance activity associated with resistance to DNA damage, and a dependence on PD-1 and LAG-3 inhibitory receptors for memory formation. These results provide insight into the identity and features of memory T cell precursors that arise during acute infection and may also have implications for improving T cell responses in settings of chronic infection and cancer. The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8+ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8+ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8+ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8+ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8+ T cell memory.