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Optimising IL-2 for Cancer Immunotherapy
Sprent Jonathan,Boyman Onur 대한면역학회 2024 Immune Network Vol.24 No.1
The key role of T cells in cancer immunotherapy is well established and is highlighted by the remarkable capacity of Ab-mediated checkpoint blockade to overcome T-cell exhaustion and amplify anti-tumor responses. However, total or partial tumor remission following checkpoint blockade is still limited to only a few types of tumors. Hence, concerted attempts are being made to devise new methods for improving tumor immunity. Currently, much attention is being focused on therapy with IL-2. This cytokine is a powerful growth factor for T cells and optimises their effector functions. When used at therapeutic doses for cancer treatment, however, IL-2 is highly toxic. Nevertheless, recent work has shown that modifying the structure or presentation of IL-2 can reduce toxicity and lead to effective anti-tumor responses in synergy with checkpoint blockade. Here, we review the complex interaction of IL-2 with T cells: first during normal homeostasis, then during responses to pathogens, and finally in anti-tumor responses.
Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells
Sprent, Jonathan,Surh, Charles D Nature Publishing Group, a division of Macmillan P 2011 Nature immunology Vol.12 No.6
Weak T cell antigen receptor (TCR) signals from contact with self ligands act in synergy with antiapoptotic signals induced by interleukin 7 (IL-7) to promote the survival of naive T cells in a resting state. The amount of background TCR signaling in naive T cells is set by post-thymic TCR tuning and operates at an intensity just below that required to induce entry into the cell cycle. Costimulation from higher concentrations of IL-7 and other common 款-chain cytokines can induce T cells to undergo homeostatic proliferation and conversion into cells with a memory phenotype; many of these memory phenotype cells may be the progeny of cells responding to self antigens. The molecular mechanisms that control the conversion of naive resting T cells into memory-phenotype cells TCR-dependent in normal animals are beginning to be understood.
The role of interleukin-2 during homeostasis and activation of the immune system
Boyman, Onur,Sprent, Jonathan Nature Publishing Group, a division of Macmillan P 2012 Nature reviews. Immunology Vol.12 No.3
Interleukin-2 (IL-2) signals influence various lymphocyte subsets during differentiation, immune responses and homeostasis. As discussed in this Review, stimulation with IL-2 is crucial for the maintenance of regulatory T (T<SUB>Reg</SUB>) cells and for the differentiation of CD4<SUP>+</SUP> T cells into defined effector T cell subsets following antigen-mediated activation. For CD8<SUP>+</SUP> T cells, IL-2 signals optimize both effector T cell generation and differentiation into memory cells. IL-2 is presented in soluble form or bound to dendritic cells and the extracellular matrix. Use of IL-2 ?? either alone or in complex with particular neutralizing IL-2-specific antibodies ?? can amplify CD8<SUP>+</SUP> T cell responses or induce the expansion of the T<SUB>Reg</SUB> cell population, thus favouring either immune stimulation or suppression.
Cho, Jae-Ho,Kim, Hee-Ok,Surh, Charles D.,Sprent, Jonathan Elsevier 2010 Immunity Vol.32 No.2
<P><B>Summary</B></P><P>T cell receptor (TCR) contact with self ligands keeps T cells alive and is shown here to cause naive CD8<SUP>+</SUP>, but not CD4<SUP>+</SUP>, T cells to be hypersensitive to certain γ<SUB>c</SUB> cytokines, notably interleukin (IL)-2, IL-15, and IL-7. Hypersensitivity of CD8<SUP>+</SUP> T cells to IL-2 was dependent on a low-level TCR signal, associated with high expression of CD5 and GM1, a marker for lipid rafts, and was abolished by disruption of lipid rafts. By contrast, CD4<SUP>+</SUP> T cells expressed low amounts of GM1 and were unresponsive to IL-2. Physiologically, sensitivity to IL-7 and IL-15 maintains survival of resting CD8<SUP>+</SUP> T cells, whereas sensitivity to IL-2 may be irrelevant for normal homeostasis but crucial for the immune response. Thus, TCR contact with antigen upregulates GM1 and amplifies responsiveness of naive CD8<SUP>+</SUP> T cells to IL-2, thereby making the cells highly sensitive to exogenous IL-2 from CD4<SUP>+</SUP> T helper cells.</P> <P><B>Graphical Abstract</B></P><P><ce:figure></ce:figure></P><P><B>Highlights</B></P><P>► Naive CD8<SUP>+</SUP> T cells proliferate in response to IL-2, IL-7, and IL-15 ► Preventing TCR-self-MHC interaction reduces responses to γ<SUB>c</SUB> cytokines ► TCR-self-MHC contact augments the density of lipid rafts on naive CD8<SUP>+</SUP> T cells ► Lipid rafts promote CD4<SUP>+</SUP> T cell-dependent responses of CD8<SUP>+</SUP> T cells</P>
Lé,tourneau, Sven,van Leeuwen, Ester M. M.,Krieg, Carsten,Martin, Chris,Pantaleo, Giuseppe,Sprent, Jonathan,Surh, Charles D.,Boyman, Onur Proceedings of the National Academy of Sciences 2010 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.107 No.5
<P>IL-2 is crucial to T cell homeostasis, especially of CD4<SUP>+</SUP> T regulatory cells and memory CD8<SUP>+</SUP> cells, as evidenced by vigorous proliferation of these cells in vivo following injections of superagonist IL-2/anti-IL-2 antibody complexes. The mechanism of IL-2/anti-IL-2 antibody complexes is unknown owing to a lack of understanding of IL-2 homeostasis. We show that IL-2 receptor α (CD25) plays a crucial role in IL-2 homeostasis. Thus, prolongation of IL-2 half-life and blocking of CD25 using antibodies or CD25-deficient mice led in combination, but not alone, to vigorous IL-2-mediated T cell proliferation, similar to IL-2/anti-IL-2 antibody complexes. These data suggest an unpredicted role for CD25 in IL-2 homeostasis.</P>
Corpuz, Theresa M.,Stolp, Jessica,Kim, Hee-Ok,Pinget, Gabriela V.,Gray, Daniel H. D.,Cho, Jae-Ho,Sprent, Jonathan,Webster, Kylie E. American Association of Immunologists 2016 Journal of Immunology Vol. No.
<P>gamma delta T cells respond to molecules upregulated following infection or cellular stress using both TCR and non-TCR molecules. The importance of innate signals versus TCR ligation varies greatly. Both innate-like IL-17-producing gamma delta T (gamma delta T-17) and IFN-gamma-producing gamma delta T (gamma delta T-IFN gamma) subsets tune the sensitivity of their TCR following thymic development, allowing robust responses to inflammatory cytokines in the periphery. The remaining conventional gamma delta T cells retain high TCR responsiveness. We determined homeostatic mechanisms that govern these various subsets in the peripheral lymphoid tissues. We found that, although innate-like gamma delta T-17 and gamma delta T-IFN gamma cells share elements of thymic development, they diverge when it comes to homeostasis. Both exhibit acute sensitivity to cytokines compared with conventional gamma delta T cells, but they do not monopolize the same cytokine. gamma delta T-17 cells rely exclusively on IL-7 for turnover and survival, aligning them with NKT17 cells; IL-7 ligation triggers proliferation, as well as promotes survival, upregulating Bcl-2 and Bcl-x(L). gamma delta T-IFN gamma cells instead depend heavily on IL-15. They display traits analogous to memory CD8(+) T cells and upregulate Bcl-x(L) and Mcl-1 upon cytokine stimulation. The conventional gamma delta T cells display low sensitivity to cytokine-alone stimulation and favor IL-7 for their turnover, characteristics reminiscent of naive alpha beta T cells, suggesting that they may also require tonic TCR signaling for population maintenance. These survival constraints suggest that gamma delta T cell subsets do not directly compete with each other for cytokines, but instead fall into resource niches with other functionally similar lymphocytes.</P>
Unique Features of Naive CD8<sup>+</sup> T Cell Activation by IL-2
Cho, Jae-Ho,Kim, Hee-Ok,Kim, Kyu-Sik,Yang, Deok-Hwan,Surh, Charles D.,Sprent, Jonathan The American Association of Immunologists, Inc. 2013 JOURNAL OF IMMUNOLOGY Vol.191 No.11
<P>IL-2 has a pervasive influence on the immune system and dictates the survival and differentiation of multiple T cell subsets, including CD4 regulatory T cells, CD4 Th cells, and CD8 memory cells. IL-2 is synthesized by T cells during the early stages of the immune response and promotes T cell expansion and effector cell generation after initial activation via TCR signaling. Based on studies with activated T cell lines maintained in vitro, IL-2 is known to activate multiple signaling pathways that show considerable overlap with the pathways elicited via the TCR. In this paper, we have examined IL-2 signaling under TCR-independent conditions, namely by culturing purified resting naive CD8 T cells with IL-2 in the absence of Ag or APC. Under these conditions, we show in this study that IL-2 elicits a unique pattern of signaling associated with strong lymphocyte-specific protein tyrosine kinase/JAK3-dependent activation of the PI3K/AKT pathway with little or no involvement of STAT5, NF-κB, or the calcineurin/NFAT pathways. Such signaling induces marked proliferation associated with rapid and selective expression of eomesodermin but not T-bet and differentiation into long-lived central memory cells after adoptive transfer.</P>