Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function

By R. Zeng, Rosanne Spolski, S. Finkelstein, Sangkon Oh, P. Kovanen, C. Hinrichs, C. Pise-Masison, M. Radonovich, J. Brady, N. Restifo and 2 more. Journal of Experimental Medicine, 2005

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Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/d5f2f244fcf97005db944339a6ce7aaf6455d960

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In Immunology

Citations in the corpus

Interleukin 12: still a promising candidate for tumor immunotherapy? (2014, methodology): “Combined use with IL-7 [130], IL-12 [120,131], and IL-21 [126,129]”
Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. (2015, background): “IL-15 demonstrated activity in syngeneic murine TRAMP (Transgenic Adenocarcinoma Mouse Prostate) C2 prostatic cancer, Pmel-1 and B16 melanoma, and MC38 and CT26 colon carcinoma models.(8,21-29) On the basis of these data, an Escherichia coli (E coli) recombinant DNA– based process was developed to p”
IL-2 Family Cytokines: New Insights into the Complex Roles of IL-2 as a Broad Regulator of T helper Cell Differentiation (2011, background): “IL-2 broadly modulates cytokine receptor expression IL-2 is well known to induce expression of both IL-2Ra [27] and IL-2Rb [28], presumably serving as a positive feedback loop, a strategy utilized by other cytokines as well, such as IL-4, IL-12, and IL-21, which also induce expression of their own r”
The biological functions of T helper 17 cell effector cytokines in inflammation. (2008, neutral): “Moreover, IL21 synergizes with IL-15 in regulation of the proliferation and activation of both naı̈ve and memory CD8 T cells (Kasaian et al., 2002; Zeng et al., 2005).”
New insights into the regulation of T cells by γc family cytokines (2009, neutral): “IL-7 and IL-15 can also function cooperatively with IL-21 to expand CD8 + T cell populations in vitro”
Death by a thousand cuts: granzyme pathways of programmed cell death. (2008, background): “IL-21 works synergistically with IL-15 to upregulate GzmA and GzmB expression in mouse CD8 T cells (30).”
Interleukin-2 at the Crossroads of Effector Responses, Tolerance, and Immunotherapy (2013, neutral): “…CD8+ splenic T cells, IL-15 is more potent than IL-2 in driving cell-cycle progression andmore effectively cooperates with IL-21 than does IL-2 (Zeng et al., 2005), whereas in antigen-activated CD8+ T cells, IL-2 more potently increases protein synthesis and cell proliferation than does IL15…”