Dual Roles of Il-15 in Maintaining Il-7RlowCcr7- Memory Cd8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/Akt Pathway

Kim, H.-R.; Hwang, K.-A.; Kang, I.

The Journal of Immunology 179(10): 6734-6740


DOI: 10.4049/jimmunol.179.10.6734
Accession: 068490656

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Recently, we identified two subsets of CCR7(-) memory CD8(+) T cells expressing high and low levels of the IL-7R alpha-chain (IL-7Ralpha) that is essential for memory T cell survival in human peripheral blood. IL-7Ralpha(low)CCR7(-) 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-7Ralpha(low)CCR7(-) memory CD8(+) T cells have increased expression of IL-2/15R beta-chain (IL-2/15Rbeta), 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-2/15Rbeta expression compared with IL-7Ralpha(high)CCR7(-) memory CD8(+) T cells. Such a cytokine chain is functional as IL-7Ralpha(low)CCR7(-) 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-7Ralpha(low) 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-7Ralpha(low)CCR7(-) 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.