Overexpression of Interleukin (IL)-7 Leads to IL-15–independent Generation of Memory Phenotype CD8+ T Cells

Kieper, William C.; Tan, Joyce T.; Bondi-Boyd, Brea; Gapin, Laurent; Sprent, Jonathan; Ceredig, Rhodri; Surh, Charles D.

doi:10.1084/jem.20020067

Cited by 258 publications

(235 citation statements)

References 34 publications

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“…Both constitutive and lymphopenia-induced proliferation of mouse T cells depend on the homeostatic cytokines IL-7 and IL-15 [15,16,[24][25][26][27]. Although the relative contributions of different cytokines to homeostatic proliferation in humans are difficult to address directly, recent reports are consistent with the view that human and murine T cells have similar requirements [13,14,21,[28][29][30][31][32].…”

Section: Discussionmentioning

confidence: 79%

Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets

et al. 2005

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Section: Discussionmentioning

confidence: 79%

Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets

et al. 2005

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“…In transgenic mice that overexpress IL-7 or IL-15, there is a substantial increase in the absolute number of T cells [27,28]. This increase is driven largely by the expansion of CD8 + CD44 high memory Tcells.…”

Section: Evidence For the Presence Of Homeostatic Cellular Cytokine 'mentioning

confidence: 99%

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

Klebanoff

Khong

Antony

et al. 2005

Trends in Immunology

404

288

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Lymphodepletion followed by adoptive cell transfer (ACT) of autologous, tumor-reactive T cells boosts antitumor immunotherapeutic activity in mouse and in humans. In the most recent clinical trials, lymphodepletion together with ACT has an objective response rate of 50% in patients with solid metastatic tumors. The mechanisms underlying this recent advance in cancer immunotherapy are beginning to be elucidated and include: the elimination of cellular cytokine 'sinks' for homeostatic γ C -cytokines, such as interleukin-7 (IL-7), IL-15 and possibly IL-21, which activate and expand tumor-reactive T cells; the impairment of CD4 + CD25 + regulatory T (Treg) cells that suppress tumorreactive T cells; and the induction of tumor apoptosis and necrosis in conjunction with antigenpresenting cell activation. Knowledge of these factors could be exploited therapeutically to improve the in vivo function of adoptively transferred, tumor-reactive T cells for the treatment of cancer.

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“…IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of IL-7 [8,9] or its administration in vivo [10] increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness.…”

Section: Introductionmentioning

confidence: 99%

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

Pearson¹,

Silva²,

Saini³

et al. 2011

Eur J Immunol

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The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Ra, we show that T-cell longevity in the absence of survival cues is not a cellintrinsic property but rather a dynamic process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Ra expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is nonlimiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting, increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms.Key words: Fitness . Homeostasis . IL-7 . T cells Supporting Information available onlineIntroduction A commonly evoked concept in studies of lymphocyte homeostasis is that of cellular fitness. Whether a cell lives or dies in a particular context, such as effector cell transition to a memory state, or survival of recent thymic emigrants entering a replete peripheral compartment, is a function of its relative fitness [1]. The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment [2][3][4]. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4 1 and CD8 1 subsets are near-identical to those in mice with both subsets [5][6][7]. Conversely, genetic over-expression of 9] or its administration in vivo [10] increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness. Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes [11]. Thus, the homeostatic fitness of a T cell and consequently whether it lives or dies in a given homeostatic context may depend on how frequently it receives survival signals such as IL-7 and how long the cell can persist in the absence of such survival signalling.Ã These authors contributed equally to this work. 3656The mechanisms by which IL-7 maintains T-cell survival, and therefore regulate cellular fitness, have been the subject of numerous studies. Many of these have focused on the transc...

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Overexpression of Interleukin (IL)-7 Leads to IL-15–independent Generation of Memory Phenotype CD8+ T Cells

Cited by 258 publications

References 34 publications

Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets

Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

IL‐7 determines the homeostatic fitness of T cells by distinct mechanisms at different signalling thresholds in vivo

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