RT Journal Article SR Electronic T1 Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage JF Science Immunology JO Sci. Immunol. FD American Association for the Advancement of Science SP eabe3702 DO 10.1126/sciimmunol.abe3702 VO 6 IS 55 A1 Johnnidis, Jonathan B. A1 Muroyama, Yuki A1 Ngiow, Shin Foong A1 Chen, Zeyu A1 Manne, Sasikanth A1 Cai, Zhangying A1 Song, Shufei A1 Platt, Jesse M. A1 Schenkel, Jason M. A1 Abdel-Hakeem, Mohamed A1 Beltra, Jean-Christophe A1 Greenplate, Allison R. A1 Ali, Mohammed-Alkhatim A. A1 Nzingha, Kito A1 Giles, Josephine R. A1 Harly, Christelle A1 Attanasio, John A1 Pauken, Kristen E. A1 Bengsch, Bertram A1 Paley, Michael A. A1 Tomov, Vesselin T. A1 Kurachi, Makoto A1 Vignali, Dario A. A. A1 Sharpe, Arlene H. A1 Reiner, Steven L. A1 Bhandoola, Avinash A1 Johnson, F. Bradley A1 Wherry, E. John YR 2021 UL http://immunology.sciencemag.org/content/6/55/eabe3702.abstract AB 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.