title: Dual roles of IL-15 in maintaining IL-7RalphalowCCR7- memory CD8+ T cells in humans via recovering the phosphatidylinositol 3-kinase/AKT pathway.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Kyung-A
authors.initials: KA
authors.lastname: Hwang
authors.forename: Insoo
authors.initials: I
authors.lastname: Kang
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology*; D007239:Infections / Q000201:enzymology / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000276:immunology; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D054400:Receptors, CCR7; D053722:Receptors, Interleukin-17 / Q000096:biosynthesis / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7; D054353:Perforin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7; D053722:Receptors, Interleukin-17; C515370:CCR7 protein, human; C109985:IL17RA protein, human; C508605:IL7 protein, human