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OX40 Costimulatory Signals Potentiate the Memory Commitment of Effector CD8⁺ T Cells¹

Seyed Fazlollah Mousavi^*, Pejman Soroosh^2,*, Takeshi Takahashi^*, Yasunobu Yoshikai, Hao Shen, Leo Lefrançois, Jannie Borst^¶, Kazuo Sugamura^* and Naoto Ishii^3,*

^* Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan; Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and ^¶ Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

A T cell costimulatory molecule, OX40, contributes to T cell expansion, survival, and cytokine production. Although several roles for OX40 in CD8⁺ T cell responses to tumors and viral infection have been shown, the precise function of these signals in the generation of memory CD8⁺ T cells remains to be elucidated. To address this, we examined the generation and maintenance of memory CD8⁺ T cells during infection with Listeria monocytogenes in the presence and absence of OX40 signaling. We used the expression of killer cell lectin-like receptor G1 (KLRG1), a recently reported marker, to distinguish between short-lived effector and memory precursor effector T cells (MPECs). Although OX40 was dispensable for the generation of effector T cells in general, the lack of OX40 signals significantly reduced the number and proportion of KLRG1^low MPECs, and, subsequently, markedly impaired the generation of memory CD8⁺ T cells. Moreover, memory T cells that were generated in the absence of OX40 signals in a host animal did not show self-renewal in a second host, suggesting that OX40 is important for the maintenance of memory T cells. Additional experiments making use of an inhibitory mAb against the OX40 ligand demonstrated that OX40 signals are essential during priming, not only for the survival of KLRG1^low MPECs, but also for their self-renewing ability, both of which contribute to the homeostasis of memory CD8⁺ T cells.

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 in part by a grant-in-aid for scientific research on priority areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and a grant-in-aid for scientific research on priority areas from the Japan Society for the Promotion of Science.

² Current address: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.

³ Address correspondence and reprint requests to Dr. Naoto Ishii, Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 Japan. E-mail address: ishiin{at}mail.tains.tohoku.ac.jp

⁴ Abbreviations used in this paper: KLRG1, killer cell lectin-like receptor G1; DC, dendritic cell; MPEC, memory precursor effector T cell; OX40L, OX40 ligand; rLM-OVA, recombinant Listeria monocytogenes expressing OVA.