Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Abstract

Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)-and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells.Here we report that 10-50 g/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short-and longlasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T-and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. IntroductionCytokines belonging to the ␥-chain family represent a promising tool for the treatment of certain human diseases in which the immune system is suppressed like HIV or cancer. Thus, boosting immunity in these patients may be beneficial and result in improved treatment. is part of the ␥-chain family of cytokines and exerts multiple effects on different populations of the immune system. For instance, it is necessary for natural killer (NK)-cell development, since IL-15-deficient mice lack NK cells 1,2 ; it acts as an NK growth factor by promoting the differentiation of CD56 ϩ cytokine-producing NK cells to CD56 Ϫ CD16 ϩ cytotoxic NK cells. 3 Conversely, IL-15 is not required for T-cell development but exerts a fundamental role in determining their survival and homeostasis in the periphery. IL-15 Ϫ/Ϫ or IL-15 receptor ␣ chain (IL-15R␣) Ϫ/Ϫ mice display slightly reduced numbers of naive T cells and a selective deficiency of memory T cells. 1,2 Indeed, IL-15 is important for memory T-cell homeostasis as it mediates the expansion and maintenance of memoryphenotype CD8 ϩ T cells 4 and the homeostatic proliferation of antigen-specific CD8 ϩ T cells, while survival is mainly mediated by IL-7 in the latter case. 4,5 IL-15 also acts on memory CD4 ϩ T cells and cooperates with IL-7 in inducing their expansion in nonlymphopenic conditions. 4 A unique biological mechanism governs IL-15 functions in vivo, as the cytokine is transpresented by cells bearing IL-15R␣ chain to neighboring cells, which in turn, express CD122 (IL-15R␤ chain) and CD132 (common ␥ chain, shared by other cytokines such as IL-2, IL-7, IL-9, and IL-21), which are necessary for IL-15 signaling in responding cells 6,7 ). Activated monocytes or dendritic cells (DCs) can express IL-15R␣ and produce the cytokine at the same time; IL-15 can thus be mounted on the receptor in intracellular compartment and then translocated to the cell surface...

Interleukin-15 administration increases graft-versus-tumor activity in recipients of haploidentical hematopoietic SCT

“…Non-human primate studies have recently shown that IL-15 administration expands memory CD8 ( þ ) and CD4 ( þ ) T, and NK cells in the peripheral blood. 27,32 Early-phase clinical studies are also underway. We believe that IL-15 will have an important role in immunotherapy, especially in improving post-transplant T-cell deficiency.…”

IL-15 delays suppression and fails to promote immune reconstitution in virally suppressed chronically SIV-infected macaques

“…16 Either fresh (BAL, LN, and Jej samples) or frozen (PBMC) cells were used for phenotyping and stimulation. PBMCs were frozen in FBS ϩ 10% DMSO and stored in liquid phase nitrogen until analysis.…”

“…In contrast, IL-15 alone did not have any effect on the level of CD8 ϩ T-cell activation ( Figure 1B). The expression of CD38 was also investigated and was found to be up-regulated by IL-15 therapy in multiple CD8ϩ T-cell memory subsets, 16 and could thus not be considered a reliable marker of the effect of ART on T-cell activation (data not shown).…”

“…14 It preferentially targets effector memory (T EM )-phenotype T cells, but, to a lesser extent, also expands T cells at earlier stages of differentiation such as central memory (T CM ) and transitional memory (T TM ) cells. 15,16 We recently demonstrated that upon administration of IL-15 to rhesus macaques, T-cell proliferation occurs in multiple lymphoid and nonlymphoid tissues of the body, including the gut. 16 In particular, T CM cells from lymphoid tissues further differentiate 16 and migrate to nonlymphoid sites upon IL-15 administration.…”

“…15,16 We recently demonstrated that upon administration of IL-15 to rhesus macaques, T-cell proliferation occurs in multiple lymphoid and nonlymphoid tissues of the body, including the gut. 16 In particular, T CM cells from lymphoid tissues further differentiate 16 and migrate to nonlymphoid sites upon IL-15 administration. 17 IL-15 can exert a dual role in the context of SIV infection depending on the phase of infection.…”