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lowCCR7– Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway1Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520
Recently, we identified two subsets of CCR7– memory CD8+ T cells expressing high and low levels of the IL-7R 
-chain (IL-7R) that is essential for memory T cell survival in human peripheral blood. IL-7RlowCCR7– memory CD8+ T cells that produce effector cytokines and perforin have impaired proliferation and survival in response to TCR triggering and IL-7, respectively. These findings raise a question of how such cells are sustained at significant numbers, >20% of peripheral CD8+ T cells, despite impaired IL-7- and TCR-mediated cell maintenance. In this study, we demonstrate that IL-7RlowCCR7– memory CD8+ T cells have increased expression of IL-2/15R β-chain (IL-2/15Rβ), which is critical for IL-15 signaling, with enhanced gene expression of T box expressed in T cells (T-bet) and eomesodermin (eomes), transcriptional factors involved in IL-2/15Rβ expression compared with IL-7RhighCCR7– memory CD8+ T cells. Such a cytokine chain is functional as IL-7RlowCCR7– memory CD8+ T cells proliferate considerably in response to IL-15. Furthermore, adding IL-15 to TCR triggering recovers impaired TCR-mediated proliferation of IL-7Rlow memory CD8+ T cells via restoring the activation of the PI3K/AKT pathway. These findings indicate that IL-15 has dual roles in maintaining IL-7RlowCCR7– memory CD8+ T cells via TCR-dependent and -independent mechanisms. Moreover, IL-15 can be useful in reviving impaired proliferative function of such memory CD8+ T cells with effector functions against infections and tumors via rescuing the PI3K/AKT pathway.
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 grants from the National Institute of Health (K08 AR49444-03), the American College of Rheumatology, the Arthritis Foundation, the American Foundation for Aging Research and Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (P30AG21342 National Institutes of Health/National Institute on Aging), and the General Clinical Research Center at Yale University (National Institutes of Health/National Center for Research Resources).
2 H.R.K. and K.A.H. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Insoo Kang, Section of Rheumatology TAC S541C, Yale School of Medicine, P.O. Box 208031, New Haven, CT 06520. E-mail address: Insoo.kang{at}yale.edu
4 Abbreviation used in this paper: 
C, -chain.
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