IL-15Rα Is a Negative Regulator of TCR-Activated Proliferation in CD4+ T Cells

Lee, Jan-Mou; Chung, Chen-Yen; Chiang, Wei-Wei; Liou, Yae-Huei; Chen, Chian-Feng; Liao, Nan‐Shih

doi:10.4049/jimmunol.173.5.3155

Cited by 6 publications

(4 citation statements)

References 37 publications

(26 reference statements)

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“…This reported phenomenon represents a general theme irrespective of the applied antigens (KLH or OVA) or immunization routes (s.c. or i.p.) used in priming and was not due to the potential defects of IL‐15Rα KO CD4 + T cells 9, 27. This is supported by the observation that replacement of CD45.1 + OT‐II CD4 + T cells in the priming of CD45.2 + mice also resulted in IL‐10 overproduction.…”

Section: Discussionmentioning

confidence: 64%

Enhanced IL‐10 production by CD4⁺ T cells primed in IL‐15Rα‐deficient mice

et al. 2011

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Section: Discussionmentioning

confidence: 64%

Enhanced IL‐10 production by CD4⁺ T cells primed in IL‐15Rα‐deficient mice

et al. 2011

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“…A previous report indicated that IL-15Rα is a negative regulator of TCR-stimulated proliferation of CD4 + T cells [68]. If so, blocking IL-15 should enhance proliferation of TCR-stimulated CD4 + T cells.…”

Section: Resultsmentioning

confidence: 96%

IL-15 Augments TCR-Induced CD4+ T Cell Expansion In Vitro by Inhibiting the Suppressive Function of CD25High CD4+ T Cells

et al. 2012

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Due to its critical role in NK cell differentiation and CD8+ T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4+ T cells. The increased levels of IL-15 found in several CD4+ T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4+ T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4+ and CD8+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4+ T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4+ T cell suppression by a gradually expanding CD25HighCD4+ T cell subset that expresses Foxp3 and originates from CD4+CD25+ Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.

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“…During AAD, IL‐15 −/− mice also showed increased numbers of CD4 + T cells and B cells in the spleen and BAL, and decreased numbers of CD8 + T cells in the spleen and lung, relative to WT controls. IL‐15Rα is a negative regulator of proliferation of CD4 + T cells . In the absence of IL‐15 signalling, CD4 + T cells hyperproliferate when stimulated via the T cell receptor.…”

Section: Discussionmentioning

confidence: 99%

IL‐15‐deficient mice develop enhanced allergic responses to airway allergen exposure

Mathias

Schramm

Guernsey

et al. 2017

Clin Experimental Allergy

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Background Interleukin-15 is a pleiotropic cytokine that is critical for the development and survival of multiple hematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+T cells. We therefore hypothesized that IL-15−/− mice will have reduced inflammatory responses during the development of allergic airway disease (AAD). Objective To determine whether IL-15−/− mice have attenuated allergic responses in a mouse model of AAD. Methods C57BL/6 wild-type (WT) and IL-15−/− mice were sensitized and challenged with ovalbumin (OVA) and the development of AAD was ascertained by examining changes in airway inflammatory responses, Th2 responses, and lung histopathology. Results Here we report that IL-15−/− mice developed enhanced allergic responses in an OVA-induced model of AAD. In the absence of IL-15, OVA-challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+T and B cells in the spleens and broncholaveolar lavage (BAL) were also observed. Examination of OVA-challenged IL-15Rα−/− animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15−/− animals to levels observed in WT mice, but had no further effects. Conclusion and Clinical Relevance These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD, which can be regulated by CD8+T cells. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK, NKT, and γδ T cells, suggesting that these cells or their subsets are dispensable for the induction of AAD in IL-15-deficient mice.

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IL-15Rα Is a Negative Regulator of TCR-Activated Proliferation in CD4+ T Cells

Cited by 6 publications

References 37 publications

Enhanced IL‐10 production by CD4⁺ T cells primed in IL‐15Rα‐deficient mice

Enhanced IL‐10 production by CD4⁺ T cells primed in IL‐15Rα‐deficient mice

IL-15 Augments TCR-Induced CD4+ T Cell Expansion In Vitro by Inhibiting the Suppressive Function of CD25High CD4+ T Cells

IL‐15‐deficient mice develop enhanced allergic responses to airway allergen exposure

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IL-15Rα Is a Negative Regulator of TCR-Activated Proliferation in CD4+ T Cells

Cited by 6 publications

References 37 publications

Enhanced IL‐10 production by CD4+ T cells primed in IL‐15Rα‐deficient mice

Enhanced IL‐10 production by CD4+ T cells primed in IL‐15Rα‐deficient mice

IL-15 Augments TCR-Induced CD4+ T Cell Expansion In Vitro by Inhibiting the Suppressive Function of CD25High CD4+ T Cells

IL‐15‐deficient mice develop enhanced allergic responses to airway allergen exposure

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Enhanced IL‐10 production by CD4⁺ T cells primed in IL‐15Rα‐deficient mice

Enhanced IL‐10 production by CD4⁺ T cells primed in IL‐15Rα‐deficient mice