A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development

Al-Shami, Amin; Spolski, Rosanne; Kelly, John; Fry, Terry J.; Schwartzberg, Pamela L.; Pandey, Akhilesh; Mackall, Crystal L.; Leonard, Warren J.

doi:10.1084/jem.20031975

Cited by 211 publications

(245 citation statements)

References 36 publications

(48 reference statements)

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“…In Rag1 À/À hosts, there is a lack of T-cell competition for other factors important for CD8 1 T-cell survival, such as DCs expressing self-peptide-MHC (spMHC) and IL-15, which could also influence the fitness of F5 T cells. Additionally, IL-7Ra is also a component of the heterodimeric thymic stromal lymphopoietin (TSLP) receptor, that has also been implicated in maintenance of naïve CD4 1 T cells [27,28], and loss of signalling through this receptor could also be contributing to death of IL-7R -F5 T cells. Therefore we directly addressed the role of IL-7 in enhancing Tcell fitness by transferring the same cells to IL-7-deficient Rag1 À/À mice.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…Much discussion has focused on species-specific actions of TSLP (11,15,24). TSLP was reported to have certain B cell and T cell-related actions in mice (10,11,25), whereas human TSLP was reported to activate DCs with only an indirect effect on CD4 ϩ T cells (15). Subsequently, studies in mice revealed that mouse TSLP could also act on DCs (11,12).…”

Section: Tslp Elevates Sensitivity Of Cd4 ϩ T Cells To Low Dose Of Il-2mentioning

confidence: 99%

“…In addition to its actions on B cells, like IL-7, mouse TSLP has roles in T cell biology (10). Specifically, TSLPR/␥ c double knockout (KO) mice have more impaired T cell development than ␥ c KO mice, T cell recovery is defective in sublethally irradiated TSLPR KO mice, TSLP increases the proliferation and survival of CD4 ϩ single positive thymocytes and peripheral T cells, and finally, peripheral TSLPR KO CD4 ϩ T cells exhibit defective expansion in ␥ c /Rag2 KO-irradiated hosts (10).…”

mentioning

confidence: 99%

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

Rochman

Watanabe

Arima

et al. 2007

The Journal of Immunology

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169

162

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Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cell homeostasis and contributes to allergic and inflammatory responses. TSLP can act directly on mouse CD4+ T cells, but in humans, the available data have indicated that TSLP receptors are not expressed on CD4+ T cells and that TSLP instead activates dendritic cells, which in turn promote the proliferation and differentiation of CD4+ T cells. We now unexpectedly demonstrate the presence of TSLP receptors on activated human CD4+ T cells. Strikingly, whereas freshly isolated peripheral blood human T cells show little if any response to TSLP, TCR stimulation allows a potent response to this cytokine. Moreover, TSLP increases the sensitivity of human CD4+ T cells to low doses of IL-2, augmenting responsiveness of these cells to TCR engagement. Our results establish that human CD4+ T cells are direct targets for TSLP.

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“…Alternatively, the absence of a large portion of the lymphocyte pool could also alter the stoichiometry of APCs available to present Ag to the responding CD8 T cells, thus enhancing memory generation in the IL-7 Ϫ/Ϫ mice. Finally, IL-7R␣ can form heterodimers with the thymic stromal lymphopoietin receptor (TSLPR) that specifically binds TSLP (27,28), a cytokine important for CD4 development and homeostasis (29,30). Signaling through the TSLPR, however, does not appear to influence IL-7R␣ expression as in vivo blocking studies using an anti-TSLP-R mAb failed to impact IL-7R␣ expression kinetics on Ag-specific CD8 T cells in both wild-type and IL-7 Ϫ/Ϫ mice following infection (data not shown).…”

Section: Il-7-deficient Environment Does Not Alter Il-7r␣ Expression mentioning

confidence: 99%

Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor α Expression and Memory CD8 T Cell Development

Klonowski

Williams

Marzo

et al. 2006

The Journal of Immunology

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Expression of IL-7Rα on a subset of Ag-specific effector CD8 T cells is believed to identify memory cell precursors. However, whether IL-7 regulates IL-7Rα expression in vivo and is responsible for selective survival of IL-7Rα+ effector cells is unknown. Our results show that in the absence of IL-7, IL-7Rα expression was extinguished on the majority of CD8 T cells responding to virus infection, sustained on a subset of effector cells transitioning to memory, and expressed at high levels by memory cells. Additionally, an IL-7-deficient environment was capable of supporting bcl-2 up-regulation and memory cell development in response to virus infection. Thus, IL-7Rα regulation occurs independently of IL-7 in responding CD8 T cells, indicating that CD8 memory T cell precursors are not selected by IL-7/IL-7Rα interactions.

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A Role for Thymic Stromal Lymphopoietin in CD4+ T Cell Development

Cited by 211 publications

References 36 publications

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

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

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor α Expression and Memory CD8 T Cell Development

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