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Protective CD8 T Cell Memory Is Impaired during Chronic CD70-Driven Costimulation¹

Klaas P. J. M. van Gisbergen^2,*, Ronald W. van Olffen^*, Josine van Beek, Koenraad F. van der Sluijs, Ramon Arens, Martijn A. Nolte^* and Rene A. van Lier^*

^* Department of Experimental Immunology and Department of Pulmonology, Academic Medical Center, Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research at CLB and Landsteiner Laboratory, Amsterdam, The Netherlands; and Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

Chronic infection results in continuous formation and exhaustion of effector CD8 T cells and in failure of memory CD8 T cell development. Expression of CD70 and other molecules that provide costimulation to T cells is maintained during chronic infection. To analyze the impact of constitutive CD70-driven costimulation, we generated transgenic mice expressing CD70 specifically on T cells. We show that CD70 promoted accumulation of CD8 T cells with characteristics strikingly similar to exhausted effector CD8 T cells found during chronic infection. CD70 on T cells provided costimulation that enhanced primary CD8 T cell responses against influenza. In contrast, memory CD8 T cell maintenance and protection against secondary challenge with influenza was impaired. Interestingly, we found no effect on the formation of either effector or memory CD4 T cells. We conclude that constitutive expression of CD70 is sufficient to deregulate the CD8 T cell differentiation pathway of acute infection reminiscent of events in chronic infection.

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 Vidi and Vici grants of the Netherlands Organization for Scientific Research.

² Address correspondence and reprint requests to Dr. Klaas P. J. M. van Gisbergen, Department of Experimental Immunology, K0-132, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail address: k.p.vangisbergen{at}amc.nl

³ Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; CM, central memory; EM, effector memory; pLN, peripheral lymph node; mLN, mediastinal lymph node; MPEC, memory precursor effector cell; SLEC, short-lived effector cell; Tg, transgenic; PD-1, programmed death protein 1; DC, dendritic cell; TCID₅₀, 50% tissue culture infective dose; BM, bone marrow; WT, wild type.

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