Selective Expansion and Partial Activation of Human NK Cells and NK Receptor-Positive T Cells by IL-2 and IL-15

Abstract

IL-2 and IL-15 are lymphocyte growth factors produced by different cell types with overlapping functions in immune responses. Both cytokines costimulate lymphocyte proliferation and activation, while IL-15 additionally promotes the development and survival of NK cells, NKT cells, and intraepithelial lymphocytes. We have investigated the effects of IL-2 and IL-15 on proliferation, cytotoxicity, and cytokine secretion by human PBMC subpopulations in vitro. Both cytokines selectively induced the proliferation of NK cells and CD56+ T cells, but not CD56− lymphocytes. All NK and CD56+ T cell subpopulations tested (CD4+, CD8+, CD4−CD8−, αβTCR+, γδTCR+, CD16+, CD161+, CD158a+, CD158b+, KIR3DL1+, and CD94+) expanded in response to both cytokines, whereas all CD56− cell subpopulations did not. Therefore, previously reported IL-15-induced γδ and CD8+ T cell expansions reflect proliferations of NK and CD56+ T cells that most frequently express these phenotypes. IL-15 also expanded CD8α+β− and Vα24Vβ11 TCR+ T cells. Both cytokines stimulated cytotoxicity by NK and CD56+ T cells against K562 targets, but not the production of IFN-γ, TNF-α, IL-2, or IL-4. However, they augmented cytokine production in response to phorbol ester stimulation or CD3 cross-linking by inducing the proliferation of NK cells and CD56+ T cells that produce these cytokines at greater frequencies than other T cells. These results indicate that IL-2 and IL-15 act at different stages of the immune response by expanding and partially activating NK receptor-positive lymphocytes, but, on their own, do not influence the Th1/Th2 balance of adaptive immune responses.

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

“…IL-21 is structurally related to IL-2 and IL-15, the cytokines that have a crucial role in thymic and peripheral T cell maturation, respectively (27,28). IL-15 regulates NK and CD8 ϩ memory cell maturation and acquisition of cytolytic activity.…”

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

“…18 Further investigations might improve on this by activation with additional cytokines like IL-15, IL-18 or IL-21. 28,[32][33][34] Nevertheless those strategies require close patient monitoring to investigate the influence of the respective cytokine on the cell sub-population in peripheral blood. Very recently, we could show that IL-2-stimulated NK-DLI but not unstimulated NK-DLI promote NK cell trafficking and changes in the distribution of leukocyte sub-populations in the peripheral blood.…”

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

“…As indicated by in vivo studies, patients who demonstrate Th2 dominance tend to develop chronic infection, whereas those with a Th1 phenotype can clear Of the ISGs analyzed, IL-15, a unique target of IRF-1, was also substantially reduced in both hepatic and T cells expressing either the entire HCV replicon or the structural proteins, and to our knowledge this is the first study reporting a repression of IL-15 in cells bearing the entire HCV replicon. IL-15 is involved in the activation and homeostatic maintenance of cells of both the innate and adaptive immune systems, playing a key role in CD8 ϩ T-cell homeostasis by promoting survival or proliferation of naive and memory phenotype CD8 T cells and in NK cell development, maturation, and survival (14,40,80). Notably, it has been reported that impaired IL-15 production is one of the mechanisms of the aberrant response of DC to IFN in HCV-infected patients (28).…”