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  • Review Article
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Harnessing the biology of IL-7 for therapeutic application

Nature Reviews Immunology volume 11, pages 330–342 (2011)Cite this article

Subjects

Key Points

  • Interleukin-7 (IL-7) is required for T cell development in mice and humans and is produced by stromal tissues rather than activated lymphocytes. Under normal conditions, IL-7 is a limiting resource for T cells, but it accumulates during lymphopenic conditions. IL-7 signals through a heterodimeric receptor consisting of the IL-7 receptor α-chain (IL-7Rα) and the common cytokine receptor γ-chain (γc).

  • IL-7 is not required for human B cell development in fetal life, but it affects early B cell progenitors and contributes to B cell development under normal conditions.

  • IL-7 has also been recently demonstrated to regulate lymphoid tissue inducer (LTi) cells, which induce the development of secondary lymphoid organs and can induce tertiary lymphoid tissue postnatally in settings of chronic inflammation.

  • In animals, IL-7 therapy enhances the effectiveness of adoptive immunotherapy for cancer, enhances vaccine responses and enhances viral clearance in the setting of acute and chronic infections.

  • In mature T cells, IL-7Rα is most highly expressed on recent thymic emigrants, maintained on naive T cells, downregulated upon T cell activation, and re-expressed on memory T cell subsets. As a result, treatment with recombinant human IL-7 (rhIL-7) preferentially expands recent thymic emigrants and naive T cells, as well as central memory T cells, but largely spares senescent T cells and regulatory T cells. This results in increased repertoire diversity following rhIL-7 therapy in humans.

  • Clinical results with rhIL-7 thus far have shown it to be well tolerated with dose-dependent increases in T cell numbers that persist long after the cytokine is cleared. Based on the pharmacological and biological properties demonstrated thus far, IL-7 is particularly well-suited as a therapy for conditions associated with lymphocyte immunodeficiency.

  • Multiple trials are ongoing or planned in HIV infection, other chronic infections (including hepatitis B and C), cancer (including as an adjuvant to immune-based therapies), post-haematopoietic stem cell transplantation and ageing.

Abstract

Interleukin-7 (IL-7) is required for T cell development and for maintaining and restoring homeostasis of mature T cells. IL-7 is a limiting resource under normal conditions, but it accumulates during lymphopaenia, leading to increased T cell proliferation. The administration of recombinant human IL-7 to normal or lymphopenic mice, non-human primates and humans results in widespread T cell proliferation, increased T cell numbers, modulation of peripheral T cell subsets and increased T cell receptor repertoire diversity. These effects raise the prospect that IL-7 could mediate therapeutic benefits in several clinical settings. This Review summarizes the biology of IL-7 and the results of its clinical use that are available so far to provide a perspective on the opportunities for clinical application of this cytokine.

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Figure 1: IL-7-mediated signalling pathways.
Figure 2: IL-7R expression by lymphocytes.
Figure 3: Distinctions between a prototypical activation cytokine (IL-2) and a prototypical homeostatic cytokine (IL-7).
Figure 4: Recombinant human IL-7 diversifies the TCR repertoire by preferential expansion of naive T cell populations and recent thymic emigrants.

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Acknowledgements

We would like to thank S. Durum for his critical review of the manuscript and his helpful discussions. This work was supported by the Intramural Research Program of the National Institutes of Health, USA.

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Authors and Affiliations

  1. Immunology Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Crystal L. Mackall

  2. Blood and Marrow Transplant Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

    Terry J. Fry

  3. Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

    Ronald E. Gress

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  1. Crystal L. Mackall
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Correspondence to Crystal L. Mackall.

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Glossary

Janus kinase–signal transducer and activator of transcription pathway

(JAK–STAT pathway). An evolutionarily conserved signalling pathway that is associated with type I and type II cytokines. Receptor ligation by these cytokines leads to a series of events that includes the recruitment and activation of JAKs and the phosphorylation of various STATs, which in turn translocate to the nucleus where they transactivate various genes involved in cell differentiation, survival, apoptosis and proliferation.

Severe combined immunodeficiency

(SCID). A primary (inherited) immunodeficiency characterized by defects in cell-mediated and humoral immune responses. Affected infants commonly die within the first year of life owing to recurrent infections. Mutations in approximately ten different genes have been described to cause this condition, but defects in the common cytokine receptor γ-chain (γc) are the most common and result in X-linked SCID. Other genes that are mutated in patients with SCID include those encoding Janus kinase 3 (JAK3), recombination activating gene 1 (RAG1) and RAG2, IL-7 receptor α-chain (IL-7Rα) and adenosine deaminase.

pro-B cell

A cell at the earliest stage of B cell development in the bone marrow. These cells are characterized by incomplete immunoglobulin heavy-chain gene rearrangement and are defined as being CD19+ cytoplasmic IgM− or, sometimes, as B220+CD43+ (by the Hardy classification scheme).

pre-B cell

A cell at a stage of B cell development in the bone marrow that is characterized by complete immunoglobulin heavy-chain gene rearrangement in the absence of immunoglobulin light-chain gene rearrangement. These cells express the pre-B cell receptor, which comprises a pseudo light chain and a heavy chain. They are phenotypically CD19+ cytoplasmic IgM+ or are sometimes defined as being B220+CD43− cell surface IgM− (by the Hardy classification scheme).

Sepsis

A systemic response to severe infection or tissue damage, leading to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability, cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death.

Delayed-type hypersensitivity

(DTH). A cellular immune response to antigen that develops over ∼24–72 hours with the infiltration of T cells and monocytes, and is dependent on the production of T helper 1 cell-specific cytokines.

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Mackall, C., Fry, T. & Gress, R. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 11, 330–342 (2011). https://doi.org/10.1038/nri2970

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