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Strength of Stimulus and Clonal Competition Impact the Rate of Memory CD8 T Cell Differentiation^1,2

Surojit Sarkar^3,*, Volker Teichgräber^4,5,*, Vandana Kalia^*, Antonio Polley, David Masopust^*, Laurie E. Harrington^5,*, Rafi Ahmed^* and E. John Wherry^6,

^* Department of Microbiology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and Immunology Program, The Wistar Institute, Philadelphia, PA 19104

The developmental pathways of long-lived memory CD8 T cells and the lineage relationship between memory T cell subsets remain controversial. Although some studies indicate the two major memory T cell subsets, central memory T (T_CM) and effector memory T (T_EM), are related lineages, others suggest that these subsets arise and are maintained independently of one another. In this study, we have investigated this issue and examined the differentiation of memory CD8 T cell subsets by tracking the lineage relationships of both endogenous and TCR transgenic CD8 T cell responses after acute infection. Our data indicate that TCR transgenic as well as nontransgenic T_EM differentiate into T_CM in the absence of Ag. Moreover, the rate of memory CD8 T cell differentiation from T_EM into the self-renewing and long-lived pool of T_CM is influenced by signals received during priming, including Ag levels, clonal competition, and/or the duration of infection. Although some T_EM appear to not progress to T_CM, the vast majority of T_CM are derived from T_EM. Thus, long-lasting, Ag-independent CD8 T cell memory results from progressive differentiation of memory CD8 T cells, and the rate of memory T cell differentiation is governed by events occurring early during T cell priming.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health (Grant AI30048 to R.A. and AI071309 and HHSN26620050030 C to E.J.W.), a grant from Fred Hutchinson Cancer Research Center, which is participating in the Collaboration for AIDS Vaccine. Discovery (CAUD) Consortium funded by the Bill and Melida Gates Foundation (to R.A.), The Ellison Medical Foundation (to E.J.W.), and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health (to E.J.W.).

² V.K. and S.S. were supported by the Elizabeth Glaser Pediatric AIDS Foundation.

³ S.S. and V.T. contributed equally to this work.

⁴ Current address: Medical Oncology, West German Cancer Center, Essen, Germany.

⁵ Current address: Department of Cell Biology, University of Alabama, Birmingham, AL 35294.

⁶ Address correspondence and reprint requests to Dr. E. John Wherry, 3601 Spruce Street, Philadelphia, PA 19104. E-mail address: jwherry{at}wistar.org

⁷ Abbreviations used in this paper: T_EM, effector memory T; LCMV, lymphocytic choriomeningitis virus; LCMV Arm, LCMV Armstrong; LN, lymph node; NP, nuclear protein; p.i., postinfection; T_CM, central memory T; VSV, vesicular stomatitis virus; VSV-Ind, VSV-Indiana.

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