The latest issue of Immunology & Cell Biology features an interesting commentary by Jared Purton and colleagues on the use of the cytokine IL-7 to enhance memory T cell responses. So far, attempts to improve DNA vaccine immunogenicity using cytokines have proven largely unsuccessful, but emerging data suggests that the timing of administration may be a critical variable. Purton and colleagues cite a recent study showing that administering IL-7 during the contraction phase of a CD8 T cell response can enhance memory CD8 T cell formation in mice, and propose that these results might be further improved using an approach they have developed which complexes IL-7 with an anti-IL-7 monoclonal antibody (both study abstracts are appended below).
Interestingly, at CROI earlier this year, data was presented from a phase I trial of IL-7 in people with HIV infection showing that administration of the cytokine was associated with changes in the functional profile of HIV-specific memory CD4 T cell responses. Although the follow-up is only short-term, the numbers of HIV-specific memory CD4 T cell capable of producing IL-2 were significantly increased among IL-7 recipients, a phenomenon not seen in studies of other cytokines. Hopefully future studies will elucidate how this relates to observations regarding the influence of IL-7 on CD8 T cell memory. A phase I trial of a glycosylated form of IL-7 with improved pharmacokinetics is slated to start soon, details can be found in the clinicaltrials.gov listing.
This issue of Immunology & Cell Biology also contains a special feature on the determination of T cell fate by dendritic cells, which includes several free access reviews including Geography and plumbing control the T cell response to infection by Kamal Khanna and Leo Lefrançois and Dendritic cell behaviour in vivo: lessons learned from intravital two-photon microscopy by Lois Cavanagh and Wolfgang Weninger.
Immunology and Cell Biology (2008) 86, 385–386; doi:10.1038/icb.2008.30
News and Commentary
Enhancing T cell memory: IL-7 as an adjuvant to boost memory T-cell generation
Jared F Purton, Chris E Martin and Charles D Surh
Correspondence: Dr JF Purton, Scripps Research Institute, IMM-26, La Jolla, CA 92037, USA.
Cytokines play a central role in regulating the homeostasis of naïve and memory T cells and their responses to pathogens. Surprisingly, not much is known about the ability of exogenously administered cytokines to affect the formation of memory T cells. In a recent study, Nanjappa et al.1 have shown that infusion of interleukin (IL)-7 during the contraction phase of a T-cell response can augment the accumulation of functional viral-specific memory T cells. As the formation of a large pool of memory T cells is the main goal of vaccination, these findings suggest that cytokines could be applied therapeutically to enhance vaccine efficacy.
J. Clin. Invest. 118(3): 1027-1039 (2008). doi:10.1172/JCI32020.
Research Article
Effects of IL-7 on memory CD8+ T cell homeostasis are influenced by the timing of therapy in mice
Som G. Nanjappa1, Jane H. Walent1, Michel Morre2 and M. Suresh1
1Department of Pathobiological Sciences, University of Wisconsin–Madison, Madison, Wisconsin, USA.
2Cytheris Inc., Issy-Les-Moulineaux, France.
Address correspondence to: M. Suresh, 2015 Linden Drive, Department of Pathobiological Sciences, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA.
Received for publication March 5, 2007, and accepted in revised form November 28, 2007.
IL-7 is integral to the generation and maintenance of CD8+ T cell memory, and insufficient IL-7 is believed to limit survival and the persistence of memory CD8+ T cells. Here, we show that during the mouse T cell response to lymphocytic choriomeningitis virus, IL-7 enhanced the number of memory CD8+ T cells when its administration was restricted to the contraction phase of the response. Likewise, IL-7 administration during the contraction phase of the mouse T cell response to vaccinia virus or a DNA vaccine potentiated antigen-specific CD8+ memory T cell proliferation and function. Qualitatively, CD8+ T cells from IL-7–treated mice exhibited superior recall responses and improved viral control. IL-7 treatment during the memory phase stimulated a marked increase in the number of memory CD8+ T cells, but the effects were transient. IL-7 therapy during contraction of the secondary CD8+ T cell response also expanded the pool of memory CD8+ T cells. Collectively, our studies show differential effects of IL-7 on memory CD8+ T cell homeostasis and underscore the importance of the timing of IL-7 therapy to effectively improve CD8+ T cell memory and protective immunity. These findings may have implications in the clinical use of IL-7 as an immunotherapeutic agent to bolster vaccine-induced CD8+ T cell memory.
J Immunol. 2008 Jun 1;180(11):7265-75.
Boyman O, Ramsey C, Kim DM, Sprent J, Surh CD.
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
IL-7, a member of the common gamma-chain family of cytokines, is essential for B and T lymphocyte development and homeostasis of mature T cell subsets. Thus, naive and memory T cells are both dependent on IL-7 for survival and homeostatic proliferation under lymphopenic conditions. In line with prior findings with IL-2, we show in this study that the biological activity of IL-7 in vivo is greatly increased by association with. Under in vivo conditions, IL-7/mAb complexes displayed 50- to 100-fold higher activity than free IL-7 and induced massive expansion of pre-B cells. IL-7/mAb complexes also increased thymopoiesis in normal mice and restored thymopoeisis in IL-7-deficient mice. For mature T cells, IL-7/mAb complexes induced marked homeostatic proliferation of both naive and memory CD4(+) and CD8(+) cell subsets even under normal T cell-replete conditions. Finally, IL-7/mAb complexes were able to enhance the magnitude of the primary response of Ag-specific naive CD8(+) cells. The strong stimulatory activity of IL-7/mAb complexes could be useful for treatment of immunodeficiency and cancer.
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