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

Jonathan B. Johnnidis, Yuki Muroyama, Shin Foong Ngiow, Zeyu Chen, Sasikanth Manne, Zhangying Cai, Shufei Song, Jesse M. Platt, Jason M. Schenkel, Mohamed Abdel-Hakeem, Jean Christophe Beltra, Allison R. Greenplate, Mohammed Alkhatim A. Ali, Kito Nzingha, Josephine R. Giles, Christelle Harly, John Attanasio, Kristen E. Pauken, Bertram Bengsch, Michael A. PaleyVesselin T. Tomov, Makoto Kurachi, Dario A.A. Vignali, Arlene H. Sharpe, Steven L. Reiner, Avinash Bhandoola, F. Bradley Johnson, E. John Wherry

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish
Article numbereabe3702
JournalScience immunology
Issue number55
StatePublished - 2021


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