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Differential Requirements for OX40 Signals on Generation of Effector and Central Memory CD4⁺ T Cells¹

Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan

Memory T cells can be divided into effector memory (T_EM) and central memory (T_CM) subsets based on their effector function and homing characteristics. Although previous studies have demonstrated that TCR and cytokine signals mediate the generation of the two memory subsets of CD8⁺ T cells, the mechanisms for generation of the CD4⁺ T_EM and T_CM cell subsets are unknown. We found that OX40-deficient mice showed a marked reduction in the number of CD4⁺ T_EM cells, whereas the number of CD4⁺ T_CM cells was normal. Adoptive transfer experiments using Ag-specific CD4⁺ T cells revealed that OX40 signals during the priming phase were indispensable for the optimal generation of the CD4⁺ T_EM, but not the CD4⁺ T_CM population. In a different transfer experiment with in vitro established CD4⁺CD44^highCD62L^low (T_EM precursor) and CD4⁺CD44^highCD62L^high (T_CM precursor) subpopulations, OX40-KO T_EM precursor cells could not survive in the recipient mice, whereas wild-type T_EM precursor cells differentiated into both T_EM and T_CM cells. In contrast, T_CM precursor cells mainly produced T_CM cells regardless of OX40 signals, implying the dispensability of OX40 for generation of T_CM cells. Nevertheless, survival of OX40-KO T_EM cells was partially rescued in lymphopenic mice. During in vitro recall responses, the OX40-KO T_EM cells that were generated in lymphopenic recipient mice showed impaired cytokine production, suggesting an essential role for OX40 not only on generation but also on effector function of CD4⁺ T_EM cells. Collectively, the present results indicate differential requirements for OX40 signals on generation of CD4⁺ T_EM and T_CM 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 by a grant-in-aid for scientific research on priority areas from the Ministry of Education, Science, Sports and Culture, the Ministry of Science and Technology, and the Japan Society for the Promotion of Science; a grant provided by Mitsubishi Pharma Research Foundation; and a grant provided by the Ichiro Kanehara Foundation.

² 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, Japan. E-mail address: ishiin{at}mail.tains.tohoku.ac.jp

³ Abbreviations used in this paper: T_EM, effector memory T cell; T_CM, central memory T cell; OX40L, OX40 ligand.

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