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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2587-2588. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fry, T. J. Search for Related Content PubMed Articles by Fry, T. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  IMMUNOBIOLOGY IL-7 comes of age Terry J. Fry NATIONAL CANCER INSTITUTE Kim and colleagues demonstrate that aging is associated with diminished numbers of IL-7R–expressing T cells and that these cells have decreased responsiveness to IL-7, with important implications for the clinical development of IL-7 as an immunomodulatory agent. Interleukin 7 (IL-7) is a pleiotropic cytokine critical for the efficient development of T and B lymphocytes. It is now clear that the importance of this cytokine for T cells does not end in the thymus. The availability of IL-7 is indispensable for the maintenance of mature T cells and for the expansion of T cells that occurs during lymphopenia. Furthermore, exogenous IL-7 can markedly enhance T-cell recovery following lymphocyte depletion, and this cytokine is being developed therapeutically as an immunorestorative agent and as an adjuvant to immune-based therapies. In spite of a rapid increase in our understanding of the biology of IL-7, little is known about the regulation of IL-7 availability in mature T-cell populations. Emerging data would imply that control of IL-7 receptor expression is critical, as has been demonstrated in developing thymocytes.1 IL-7 uses the common cytokine receptor chain c and the IL-7R chain that it shares with thymic stromal lymphopoietin. Since c is ubiquitously expressed on mature T cells, intact IL-7 signaling is critically dependent on the presence of IL-7R. Indeed, this receptor component is not present on all mature T-cell subsets, suggesting that regulation of expression is important. In contrast to other cytokines such as IL-2, T-cell receptor and IL-7 signaling results in down-regulation of the IL-7R chain, and it has been suggested that this allows for efficient sharing of an important limiting resource for T cells.2 In addition, murine models have indicated that maintenance of IL-7R on a small subset of effector T cells determines the generation of the central memory pool.3 Thus, the existing data would indicate that the tight control of IL-7 expression plays a critical role in efficient maintenance of mature T cells. View larger version (56K): [in this window] [in a new window]   Kim and colleagues demonstrate that aging, like HIV, is associated with the accumulation of T cells expressing low levels of IL-7R. While this limits the portion of cells capable of responding to IL-7, diversification of the repertoire may still occur due to preferential expansion of T cells expressing higher levels of IL-7R remaining in the naive pool. Illustration by Marie Dauenheimer.   Recently, it has been demonstrated that low levels of IL-7R are characteristic of HIV infection,4 and murine studies have indicated that this may be due to chronic antigen exposure.5 This has obvious implications for the potential use of IL-7 as a treatment following lymphopenia, but it is not entirely clear what the impact of changes in expression of IL-7R will have on therapeutic responses. In this issue of Blood, Kim and colleagues demonstrate that, like HIV, the immunodeficiency of aging is associated with an increased frequency of IL-7Rlow cells and that these T cells are phenotypic of senescent, antigen-experienced cells. Of importance, this paper also provides the novel observation that the decreased expression of IL-7 receptor results in decreased survival and proliferation in response to IL-7 in vitro. For these cells, it appears that other cytokines such as IL-15 may be important for survival. Finally, as would be predicted, the repertoire of the antigen-experienced, IL-7Rlow subset was reduced in both elderly and young individuals, but young individuals showed greater diversity in the effector memory IL-7Rhigh subset. As pointed out by the authors, this may have implications for the pool of T cells expanded by therapeutic IL-7 in the aged population. However, naive T cells also express high levels of IL-7R, contain the most diverse repertoire, and, although reduced in number in the elderly, may be preferentially expanded by IL-7 (see figure). Ultimately, clinical trials will be needed to determine whether the quantitative decrease in responses to IL-7 that may result from an increased number of IL-7Rlow T cells will hinder clinical benefit or if the preferential expansion of higher quality T cells with a diverse repertoire will overcome the diminished number of cells responding to IL-7 therapy. The paper by Kim et al provides important clues. Footnotes Comment on Kim et al, page 2855 References Munitic I, Williams JA, Yang Y, et al. Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis. Blood. 2004;104: 4165-4172.[Abstract/Free Full Text] Park JH, Yu Q, Erman B, et al. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004;21: 289-302.[CrossRef][Medline] [Order article via Infotrieve] Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol. 2003;4: 1191-1198.[CrossRef][Medline] [Order article via Infotrieve] Rethi B, Fluur C, Atlas A, et al. Loss of IL-7Ralpha is associated with CD4 T-cell depletion, high interleukin-7 levels and CD28 down-regulation in HIV infected patients. Aids. 2005;19: 2077-2086.[Medline] [Order article via Infotrieve] Lang KS, Recher M, Navarini AA, et al. Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation. Eur J Immunol. 2005;35: 738-745.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Altered IL-7R expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses Hang-Rae Kim, Myung Sun Hong, Jin Myung Dan, and Insoo Kang Blood 2006 107: 2855-2862. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fry, T. J. Search for Related Content PubMed Articles by Fry, T. J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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