TSLP: An Epithelial Cell Cytokine that Regulates T Cell Differentiation by Conditioning Dendritic Cell Maturation

Liu, Yong Jun; Soumelis, Vasilli; Watanabe, Norihiko; Ito, Tomoki; Wang, Yui Hsi; Malefyt, René de Waal; Ōmori, Makoto; Zhou, Baohua; Ziegler, Steven F.

doi:10.1146/annurev.immunol.25.022106.141718

Cited by 565 publications

(540 citation statements)

References 101 publications

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“…org). Thymic stromal lymphopoietin (TLSP), selectively induced more than fourfold in macrophages in response to P. gingivalis LPS, is considered a factor indirectly involved in Th2 cell generation 30 and only monocytes upregulated their expression of IL-18 (more than threefold), a Th1-biasing cytokine. In addition to the dominant proinflammatory cytokines, which suggest a bias toward Th17 lineage polarization, several co-stimulatory molecules were also up-regulated in the derivative myeloid cell populations, including CD80, CD83, CD44, CD69, CD58/LFA-3.…”

Section: Cytokines and Co-stimulatory Molecules Associated With Innatmentioning

confidence: 99%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigenpresenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation.

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Section: Cytokines and Co-stimulatory Molecules Associated With Innatmentioning

confidence: 99%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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“…TSLP is homologous to IL7 and is produced by the cells of epithelial origin in the thymus, lung, gut and skin. 12 Apart from an indirect effect of TSLP-activated dendritic cells on CD4 þ T-cell homeostasis 13 and T-regulatory cell development in the thymus, 14 Rochman et al 15 recently demonstrated a direct effect of TSLP on activated CD4 þ cells.…”

Section: Introductionmentioning

confidence: 99%

Variation in IL7R predisposes to sarcoid inflammation

et al. 2009

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Sarcoidosis is a chronic granulomatous disorder characterized by a massive influx of Th1 lymphocytes. Both naive and memory T cells express high levels of interleukin 7 receptor-a (IL7Ra), encoded by the IL7R gene. The purpose of this study was to investigate the role of the IL7R gene region in susceptibility to sarcoidosis. Six common single-nucleotide polymorphisms (SNPs) spanning IL7R were genotyped and analyzed in 475 sarcoidosis patients and 465 healthy controls. Replication of one significant associated SNP was carried out in 206 independent sarcoidosis patients, 127 controls and 126 patients with Lö fgren's disease. The rs10213865 SNP was associated with sarcoidosis (P ¼ 0.008), and in silico analysis showed a complete linkage (r 2 ¼ 1, D 0 ¼ 1) with a functional nonsynonymous coding SNP in exon 6 (rs6897932, T244I). Combined analysis of 663 individuals with sarcoidosis and 586 controls (homozygous carriers of risk allele, P ¼ 5 Â 10 À4 , odds ratio ¼ 1.49 (1.19-1.86)) provided strong statistical support for a genuine association of IL7R with the risk of sarcoidosis. In addition, we report the same trend between variation in the IL7R gene and patients with Lö fgren's disease, suggesting that variation in IL7R may confer general risk for developing granulomatous lung disease.

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“…Increased TSLP levels are associated with airway inflammatory disease and atopic dermatitis in humans and mice (1,(3)(4)(5). In addition, TSLP regulates intestinal immunity and inflammation (6) and is important in helminth infections (6-8).…”

mentioning

confidence: 99%

“…T hymic stromal lymphopoietin (TSLP) is a cytokine produced by stromal cells, epithelial cells, fibroblasts, keratinocytes, and basophils (1)(2)(3). Increased TSLP levels are associated with airway inflammatory disease and atopic dermatitis in humans and mice (1,(3)(4)(5).…”

mentioning

confidence: 99%

Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7–induced signaling

Rochman

Kashyap

Robinson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays essential roles in allergic/inflammatory skin and airway disorders, in helminth infections, and in regulating intestinal immunity. TSLP signals via IL-7Rα and a specific TSLPR subunit that is highly related to the common cytokine receptor γ chain, γ c . Although TSLP has effects on a broad range of hematopoetic cells and can induce STAT5 phosphorylation, TSLP was reported to not signal via JAK kinases, and the mechanism by which TSLP regulates STAT5 phosphorylation has been unclear. We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4 + T cells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7. We also show that just as JAK1 interacts with IL-7Rα, JAK2 is associated with TSLPR protein. Moreover, we demonstrate the importance of STAT5 activation for TSLPmediated survival and proliferation of CD4 + T cells. These findings clarify the basis for TSLP-mediated signaling and provide an example wherein a cytokine uses JAK1 and JAK2 to mediate the activation of STAT5.T hymic stromal lymphopoietin (TSLP) is a cytokine produced by stromal cells, epithelial cells, fibroblasts, keratinocytes, and basophils (1-3). Increased TSLP levels are associated with airway inflammatory disease and atopic dermatitis in humans and mice (1,(3)(4)(5). In addition, TSLP regulates intestinal immunity and inflammation (6) and is important in helminth infections (6-8). TSLP is closely related to IL-7, another stromal factor. IL-7 signals via IL-7Rα and the common cytokine receptor γ chain, γ c (9, 10), a protein that is also a critical component of the receptors for and is mutated in humans with X-linked severe combined immunodeficiency (12). In contrast, TSLP signals via IL-7Rα and a specific subunit, TSLPR, that is highly related to γ c (13,14). IL-7 is known to critically control the development, expansion, and survival of naive and memory T cells, thereby regulating the number of mature T cells and maintaining lymphoid homeostasis (11). TSLP can directly act on both mouse and human CD4 + and CD8 + T cells (15-18) and contributes to Tcell lymphopoiesis and homeostasis (15,18,19). However, whereas IL-7 induces proliferation and survival of mouse naive T cells, TSLP preferentially promotes survival, with less of an effect on the proliferation of these cells (15,18). Consistent with this, bone marrow-derived IxN/2B cells, which express TSLPR and IL-7Rα and respond to both TSLP and IL-7 to induce STAT5 phosphorylation, potently proliferate in response to IL-7 but not TSLP (20).Although both IL-7 and TSLP are essential in the mouse for normal B-cell lymphopoesis in vivo (15, 19), IL-7 plays a greater role, as evidenced by the profound B-cell lymphopenia in the absence of IL-7 (21). IL-7 preferentially promotes the generation of B220 + /IgM − pre-B cells from fetal liver lymphocyte precursors, whereas TSLP mediates production of B220 + /IgM + immature B cells (22,23). Interestingly, n...

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TSLP: An Epithelial Cell Cytokine that Regulates T Cell Differentiation by Conditioning Dendritic Cell Maturation

Cited by 565 publications

References 101 publications

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Variation in IL7R predisposes to sarcoid inflammation

Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7–induced signaling

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