HGNC Approved Gene Symbol: TSLP
Cytogenetic location: 5q22.1 Genomic coordinates (GRCh38) : 5:111,070,062-111,078,026 (from NCBI)
Several cytokines, including interleukin-7 (IL7; 146660), play a key role in the development of B lymphocytes. TSLP is a member of this family of B cell-stimulating factors (Reche et al., 2001).
By EST and genomic database screening for sequences similar to IL7, followed by screening a lung fibroblast sarcoma cDNA library, Reche et al. (2001) obtained a cDNA encoding TSLP. The deduced 159-amino acid protein, which is only 43% identical to mouse Tslp, contains a 28-residue signal sequence, 6 cysteines, and 2 N-glycosylation sites. SDS-PAGE analysis showed expression of a 23-kD protein, larger than the predicted 15 kD, suggesting that TSLP is glycosylated. PCR analysis of a panel of cDNA libraries and cultured cell lines indicated that expression of a 1.3-kb TSLP transcript may be restricted to a few lung libraries. Reche et al. (2001) also identified TSLP receptor, which is composed of TSLPR (CRLF2; 300357) and IL7R (146661) subunits. Dendritic cells (DCs) and monocytes coexpress IL7R and TSLPR.
Quentmeier et al. (2001) also cloned and characterized TSLP. They noted the presence of 7 basic C-terminal amino acids (KKRRKRK) in the protein and that 6 of the 7 cysteines in the mouse protein (those involved in disulfide bond formation) are conserved in human, whereas the sites for N-glycosylation are distinct. Northern blot analysis revealed wide expression of an approximately 1.1-kb transcript, with highest levels in heart, liver, testis, and prostate.
Using radiation hybrid analysis, Quentmeier et al. (2001) mapped the TSLP gene to chromosome 5 in a region showing homology of synteny to mouse chromosome 18, where the mouse Tslp gene is localized.
Hartz (2014) mapped the TSLP gene to chromosome 5q22.1 based on an alignment of the TSLP sequence (GenBank AF338732) with the genomic sequence (GRCh38).
Reche et al. (2001) showed that incubation of DCs or monocytes with TSLP enhanced the expression of CCL17 (601520), CCL18 (603757), CCL22 (602957), and CCL19 (602227). IL7, on the other hand, induced expression of CCL17, CCL22, and CCL19, but also CXCL8 (146930), CXCL7 (121010), CXCL5 (600324), CXCL1 (155730), CXCL2 (139110), and CXCL3 (139111). Functional analysis indicated that TSLP enhances the DC maturation process, as evidenced by upregulation of DC markers and costimulatory molecules and stronger T-cell proliferation.
By screening myeloid cell lines, Quentmeier et al. (2001) established that an acute myeloid leukemia line, MUTZ-3, responds by proliferating in response to TSLP. TSLP also inhibited apoptosis in these cells. Proliferation in response to TSLP could not be attributed to the production of other growth factors tested and could be inhibited by relatively high concentrations of anti-IL7R. TSLP, like IL7, stimulated phosphorylation of STAT5 (601511), but unlike IL7, it did not activate JAK3 (600173). TSLP did not phosphorylate mitogen-activated protein kinases (e.g., ERK1; 601795).
By flow cytometric analysis, Soumelis et al. (2002) showed that TSLP-activated DCs (TSLP-DCs) express higher levels of HLA-DR and DCLAMP (605883) than do nonactivated or IL7-activated DCs, and that TSLP-DCs induce marked proliferation and expansion of allogeneic naive CD4 (186940)-positive T cells. Quantitative mRNA screening and ELISA analysis showed that TSLP-DCs do not produce detectable proinflammatory cytokines, but do produce high levels of TARC (CCL17) and MDC (CCL22) chemokines, which preferentially attract CCR4 (604836)-expressing Th2 lymphocytes. TSLP-DCs induced CD4 cells to produce high amounts of IL13 (147683), IL5 (147850), and the proinflammatory cytokine tumor necrosis factor (TNF; 191160), but only low amounts of IL10 (124092) and gamma-interferon (IFNG; 147570). RT-PCR analysis did not detect TSLP in most hemopoietic cells, the exception being mast cells. Keratinocytes, epithelial cells, smooth muscle cells, and lung fibroblasts also expressed high levels of TSLP. Within tonsils, highest levels were in crypt epithelial cells. Soumelis et al. (2002) suggested that TSLP may contribute to constitutive inflammation in this tissue and sporadic inflammation in squamous epithelium. Immunohistochemical analysis of allergic inflammatory tissue showed high expression of TSLP in keratinocytes of acute and chronic atopic dermatitis lesions, but no expression in normal skin. Strong TSLP expression in atopic dermatitis was associated with the disappearance of langerin (604862)-positive Langerhans cells within the epidermis and the concurrent appearance of many DCLAMP-activated DCs within the dermis, many of which expressed langerin. Soumelis et al. (2002) proposed that TSLP expression by keratinocytes in atopic dermatitis lesions may contribute directly to the activation of Langerhans cells, which may migrate into the dermis and then the draining lymph nodes where they can prime allergen-specific Th2 responses.
Watanabe et al. (2005) reported that human Hassall corpuscles express TSLP. Human TSLP activates thymic CD11c+ (151510) dendritic cells to express high levels of CD80 (112203) and CD86 (601020). These TSLP-conditioned cells are then able to induce the proliferation and differentiation of CD4+/CD8-(186910)/CD25-(147730) thymic T cells into CD4+/CD25+/FOXP3+ (300292) regulatory T cells. This induction depends on peptide-MHC class II interactions and the presence of CD80 and CD86 as well as IL2 (147680). Immunohistochemistry studies revealed that CD25+/CTLA4+(123890) regulatory T cells associate in the thymic medulla with activated or mature dendritic cells and TSLP-expressing Hassall corpuscles. Watanabe et al. (2005) concluded that Hassall corpuscles have a critical role in dendritic cell-mediated secondary positive selection of medium to high affinity self-reactive T cells, leading to the generation of CD4+/CD25+ regulatory T cells within the thymus.
Siracusa et al. (2011) demonstrated that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore TH2-cell-dependent immunity in vivo. TSLP acted directly on bone marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL3 (147740)-IL3R (see 308385)-sufficient and -deficient environments, and genomewide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic esophagitis (see 610247) patients were distinct from classical basophils. Siracusa et al. (2011) concluded that collectively, their studies identified previously unrecognized heterogeneity within the basophil cell lineage and indicated that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil hematopoiesis and eliciting a population of functionally distinct basophils that promote TH2 cytokine-mediated inflammation.
Wilson et al. (2013) found that Tslp was secreted by keratinocytes and that it activated dorsal root ganglia (DRG) sensory neurons to evoke an itch response in mice. Tslp-evoked itch did not require lymphocytes, mast cells, or cytokines. Use of chemical inhibitors and knockout mice revealed that secretion of Tslp by keratinocytes required Nfat (see 600489) activation-dependent Tslp expression, followed by calcium signaling via Par2 (F2RL1; 600933), Orai1 (610277), and Stim1 (605921). The itch response via DRG neuronal activation required Tslp receptor, the ion channel Trpa1 (604775), and phospholipase C (see 172420) signaling. Application of Tslp directly increased intracellular calcium in DRG neurons via Trpa1 channels. Pharmacologic activation of store-operated calcium channels caused robust TSLP expression and secretion by human cutaneous and airway epithelial cells.
For discussion of a possible association between variation in the TSLP gene and eosinophilic esophagitis, see EOE2 (613412).
Using mice deficient in Il7r and/or the common cytokine receptor gamma chain, Il2rg (308380), Vosshenrich et al. (2003) determined the cytokines responsible for fetal and perinatal lymphopoiesis in the absence of Il7. Fetal and perinatal B-cell lymphopoiesis occurred in the bone marrow of Il2rg -/- mice until 12 weeks of age, but it was absent in Il7r -/- mice by 4 weeks of age. Lymphopoiesis in Il7r -/- mice was restricted to fetal liver and was dependent on the presence of Tslp. The residual lymphopoiesis that occurred in Il7r -/- mice was dependent on Flk2 (136351). Vosshenrich et al. (2003) concluded that TSLP is the main factor driving IL7-independent fetal and perinatal lymphopoiesis, although FLK2 is involved.
Using a mouse model of allergic skin inflammation elicited by repeated epicutaneous (EC) sensitization with ovalbumin (OVA) to tape-stripped skin, which mimics the scratching-inflicted injury associated with atopic dermatitis (see 603165), He et al. (2008) found that Tslpr -/- mice had reduced inflammation, with fewer eosinophils and local Th2 cytokine expression, but unchanged splenocyte secretion of these cytokines. Addition of Tslp significantly enhanced Th2 cytokine secretion in vitro by targeting Tslpr on antigen-specific T cells. Intradermal injection of anti-Tslp blocked the development of allergic skin inflammation after EC antigen challenge of OVA-immunized wildtype mice. He et al. (2008) proposed that TSLP is essential for antigen-driven Th2 cytokine secretion by skin-infiltrating effector T cells.
Hartz, P. A. Personal Communication. Baltimore, Md. 10/31/2014.
He, R., Oyoshi, M. K., Garibyan, L., Kumar, L., Ziegler, S. F., Geha, R. S. TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc. Nat. Acad. Sci. 105: 11875-11880, 2008. [PubMed: 18711124] [Full Text: https://doi.org/10.1073/pnas.0801532105]
Quentmeier, H., Drexler, H. G., Fleckenstein, D., Zaborski, M., Armstrong, A., Sims, J. E., Lyman, S. D. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia 15: 1286-1292, 2001. [PubMed: 11480573] [Full Text: https://doi.org/10.1038/sj.leu.2402175]
Reche, P. A., Soumelis, V., Gorman, D. M., Clifford, T., Liu, M., Travis, M., Zurawski, S. M., Johnston, J., Liu, Y.-J., Spits, H., de Waal Malefyt, R., Kastelein, R. A., Bazan, J. F. Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J. Immun. 167: 336-343, 2001. [PubMed: 11418668] [Full Text: https://doi.org/10.4049/jimmunol.167.1.336]
Siracusa, M. C., Saenz, S. A., Hill, D. A., Kim, B. S., Headley, M. B., Doering, T. A., Wherry, E. J., Jessup, H. K., Siegel, L. A., Kambayashi, T., Dudek, E. C., Kubo, M., Cianferoni, A., Spergel, J. M., Ziegler, S. F., Comeau, M. R., Artis, D. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477: 229-233, 2011. [PubMed: 21841801] [Full Text: https://doi.org/10.1038/nature10329]
Soumelis, V., Reche, P. A., Kanzler, H., Yuan, W., Edward, G., Homey, B., Gilliet, M., Ho, S., Antonenko, S., Lauerma, A., Smith, K., Gorman, D., Zurawski, S., Abrams, J., Menon, S., McClanahan, T., de Waal-Malefyt, R., Bazan, F., Kastelein, R. A., Liu, Y.-J. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nature Immun. 3: 673-680, 2002. [PubMed: 12055625] [Full Text: https://doi.org/10.1038/ni805]
Vosshenrich, C. A. J., Cumano, A., Muller, W., Di Santo, J. P., Vieira, P. Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nature Immun. 4: 773-779, 2003. [PubMed: 12872121] [Full Text: https://doi.org/10.1038/ni956]
Watanabe, N., Wang, Y.-H., Lee, H. K., Ito, T., Wang, Y.-H., Cao, W., Liu, Y.-J. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436: 1181-1185, 2005. [PubMed: 16121185] [Full Text: https://doi.org/10.1038/nature03886]
Wilson, S. R., The, L., Batia, L. M., Beattie, K., Katibah, G. E., McClain, S. P., Pellegrino, M., Estandian, D. M., Bautista, D. M. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155: 285-295, 2013. [PubMed: 24094650] [Full Text: https://doi.org/10.1016/j.cell.2013.08.057]