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Heterodimeric IL-15 regulates the differentiation and survival of different populations of memory T cells and the balance of effector and regulatory cells
© Pavlakis et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
The common γ-chain cytokine interleukin-15 (IL-15) regulates immune homeostasis and the fate of many lymphocyte subsets, and holds potential in fighting infections and cancer. We have previously showed that co-expression of IL-15 and IL-15 Receptor alpha (IL-15Rα) in the same cell allows for efficient production and secretion of bioactive IL-15/IL-15Rα heterodimer, whereas single-chain IL-15 is unstable. This led to the hypothesis that the physiologically relevant molecule in vivo is the heterodimer. Consistent with this hypothesis, we determined that the IL-15 found in the plasma of mice and humans is the heterodimer. Repeated subcutaneous administration of purified IL-15 heterodimers in macaques and mice resulted in sustained plasma IL-15 levels and in dose-dependent expansion of NK and T cells in blood and tissues, demonstrating pharmacokinetics and in vivo bioactivity superior to monomer IL-15. Even at a dose of 50 µg/Kg, the cytokine was well tolerated by macaques with no major side effects. IL-15 heterodimer promotes the preferential expansion of CD8+NK and CD8+ and CD4+ effector T (Teffs) cells, without preferentially affecting Tregs. As a result, sustained IL-15 levels are associated with lower relative frequency of Tregs and an increased ratio of Teff/Tregs in lymphoid tissues and in transplanted mouse colon carcinoma tumors. IL-15 knock-out (KO) mice were used to evaluate the contribution of IL-15 in the regulation of general and vaccine-induced memory T cells. Both CD4 and CD8 CD44hi Tem cells accumulate in IL-15 KO mice, consistent with the hypothesis that IL-15 is involved in the transition of effector cells to long-term central memory pool. Similar to the total Tem population, vaccine-induced Tem cells persist for longer periods of time in the absence of IL-15, providing evidence of a block in transition to long-term memory. In the absence of IL-15 Tcm cells are not sustained and there is evidence of increased apoptosis of these cells. These experiments provide information on the diverse effects of Heterodimeric IL-15 on different subpopulations of lymphocytes and support the hypothesis that IL-15 is required at multiple steps of memory T cell life cycle for the survival or differentiation of specific cell populations.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.