Thymic stromal lymphopoietin

Last updated
TSLP
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TSLP , thymic stromal lymphopoietin
External IDs OMIM: 607003 MGI: 1855696 HomoloGene: 81957 GeneCards: TSLP
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_033035
NM_138551

NM_021367

RefSeq (protein)

NP_149024
NP_612561

NP_067342

Location (UCSC) Chr 5: 111.07 – 111.08 Mb Chr 18: 32.95 – 32.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Thymic stromal lymphopoietin (TSLP) is a protein belonging to the cytokine family. It is known to play an important role in the maturation of T cell populations through activation of antigen-presenting cells.

Contents

TSLP is produced mainly by non-hematopoietic cells such as fibroblasts, epithelial cells and different types of stromal or stromal-like cells.[ citation needed ]

Gene ontology

TSLP production has been observed in various species, including humans and mice. In humans TSLP is encoded by the TSLP gene. [5] [6] Alternative splicing of this gene results in two transcript variants. [6]

Function

It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes [ citation needed ] and enhances the maturation of myeloid (CD11c+) dendritic cells. [7] TSLP has also been shown to activate the maturation of a specific subset of dendritic cells located within the epidermis, called Langerhans cells. [8] Within the thymus TSLP activation of both myeloid and plasmacytoid (CD123+) dendritic cells results in the production of regulatory T cells. [9] [10]

Signaling

Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11) TSLP wiki 5j11.png
Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11)

TSLP signals through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor CRLF2 (also known as TSLP receptor, TSLP-R) and the IL-7R alpha chain. [12] After binding STAT5 phosphorylation is induced, resulting in the expression of downstream transcription factors. [13]

Disease

TSLP expression is linked to many disease states including asthma, [14] inflammatory arthritis, [15] atopic dermatitis, [8] eczema, eosinophilic esophagitis and other allergic states. [16] [17] The factors inducing the activation of TSLP release are not clearly defined.

Asthma

Expression of TSLP is enhanced under asthma-like conditions (aka Airway HyperResponsiveness or AHR model in the mouse), conditioning APCs in order to orient the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway).[ citation needed ] The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways.[ citation needed ]

Inflammatory arthritis

Atopic dermatitis

TSLP-activated Langerhans cells of the epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis. [8] It is thought that by understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema. [18]

Inhibition

The TSLP signaling axis is an attractive therapeutic target. Amgen's Tezepelumab, a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma. [19] [20] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed. [21] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface, [22] natural products [23] and computational fragment-based screening. [24]

Related Research Articles

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References

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Further reading