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 ] These cells are located in regions where TSLP activity is required.

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

TSLP signals through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor CRLF2 and the IL-7R alpha chain. After binding STAT5 phosphorylation is induced, resulting in the expression of downstream transcription factors. [11]

Disease

TSLP expression is linked to many disease states including asthma, [12] inflammatory arthritis, [13] atopic dermatitis, [8] eczema, eosinophilic esophagitis and other allergic states. [14] [15] 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 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. [16]

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. [17] [18] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed. [19] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface, [20] natural products [21] and computational fragment-based screening. [22]

Related Research Articles

Dendritic cell Accessory cell of the mammalian immune system

Dendritic cells (DCs) are antigen-presenting cells of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.

Interleukin 21 Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

Interleukin 25 Cytokine that belongs to the IL-17 cytokine family

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.

Interleukin 17

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

CCL18

Chemokine ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.

OX40L is the ligand for OX40 and is stably expressed on many antigen-presenting cells such as DC2s, macrophages, and activated B lymphocytes.

C-C chemokine receptor type 7

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21).

PD-L1

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.

CD83

CD83 is a human protein encoded by the CD83 gene.

LIGHT (protein) Secreted protein of the TNF superfamily

LIGHT, also known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily. It is recognized by herpesvirus entry mediator (HVEM), as well as decoy receptor 3.

NCR3

Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. NCR3 has also been designated as CD337 and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).

TREM1

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a protein that in humans is encoded by the TREM1 gene. TREM-1 is a surface receptor that amplifies inflammatory processes in vitro.

KLRB1

Killer cell lectin-like receptor subfamily B, member 1, also known as KLRB1, NKR-P1A or CD161, is a human gene.

LAG3

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

CRLF2

Cytokine receptor-like factor 2 is a protein that in humans is encoded by the CRLF2 gene. It forms a ternary signaling complex with TSLP and interleukin-7 receptor-α, capable of stimulating cell proliferation through activation of STAT3, STAT5 and JAK2 pathways and is implicated in the development of the hematopoietic system. Rearrangement of this gene with immunoglobulin heavy chain gene (IGH), or with P2Y purinoceptor 8 gene (P2RY8) is associated with B-progenitor- and Down syndrome- acute lymphoblastic leukemia (ALL).

Interleukin-7 receptor-α

Interleukin-7 receptor subunit alpha (IL7R-α) also known as CD127 is a protein that in humans is encoded by the IL7R gene.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

In cell biology, TH9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.

Dipyaman Ganguly is an Indian physician-scientist immunologist and cell biologist, currently a Principal Scientist and Swarnajayanthi Fellow at the CSIR-Indian Institute of Chemical Biology (IICB). He heads the Dendritic Cell Laboratory of IICB, popularly known as Ganguly Lab, where he hosts several researchers involved in research on regulation of innate Immunity and pathogenesis of inflammatory disorders.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145777 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024379 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD (August 2001). "Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation". Leukemia. 15 (8): 1286–92. doi: 10.1038/sj.leu.2402175 . PMID   11480573.
  6. 1 2 "Entrez Gene: TSLP thymic stromal lymphopoietin".
  7. Reche PA, Soumelis V, Gorman DM, Clifford T, Travis M, Zurawski SM, et al. (July 2001). "Human thymic stromal lymphopoietin preferentially stimulates myeloid cells". Journal of Immunology. 167 (1): 336–43. doi: 10.4049/jimmunol.167.1.336 . PMID   11418668.
  8. 1 2 3 Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N (April 2007). "Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells". The Journal of Allergy and Clinical Immunology. 119 (4): 982–90. doi:10.1016/j.jaci.2007.01.003. PMID   17320941.
  9. Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ (August 2005). "Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus". Nature. 436 (7054): 1181–5. Bibcode:2005Natur.436.1181W. doi:10.1038/nature03886. PMID   16121185. S2CID   4387582.
  10. Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, et al. (March 2010). "Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus". Journal of Immunology. 184 (6): 2999–3007. doi:10.4049/jimmunol.0804106. PMC   3325785 . PMID   20173030.
  11. Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF (December 1999). "Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction". Journal of Immunology. 163 (11): 5971–7. PMID   10570284.
  12. Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. (June 2005). "Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity". Journal of Immunology. 174 (12): 8183–90. doi: 10.4049/jimmunol.174.12.8183 . PMID   15944327.
  13. Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, et al. (May 2007). "A possible role for TSLP in inflammatory arthritis". Biochemical and Biophysical Research Communications. 357 (1): 99–104. doi:10.1016/j.bbrc.2007.03.081. PMID   17416344.
  14. Soumelis V, Liu YJ (February 2004). "Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation". Springer Seminars in Immunopathology. 25 (3–4): 325–33. doi:10.1007/s00281-003-0152-0. PMID   14999427. S2CID   9713181.
  15. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. (July 2002). "Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP" (PDF). Nature Immunology. 3 (7): 673–80. doi:10.1038/ni805. PMID   12055625. S2CID   9648786.
  16. Demehri S, Morimoto M, Holtzman MJ, Kopan R (May 2009). "Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma". PLOS Biology. 7 (5): e1000067. doi:10.1371/journal.pbio.1000067. PMC   2700555 . PMID   19557146. Lay summary BBC News.{{cite journal}}: Cite uses deprecated parameter |lay-url= (help)
  17. "Tezspire- tezepelumab-ekko injection, solution". DailyMed. Retrieved 24 December 2021.
  18. "Tezspire (tezepelumab) approved in the US for severe asthma". AstraZeneca (Press release). 17 December 2021. Retrieved 17 December 2021.
  19. Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, et al. (April 2017). "Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma". Nature Communications. 8: 14937. Bibcode:2017NatCo...814937V. doi:10.1038/ncomms14937. PMC   5382266 . PMID   28368013.
  20. Park S, Park Y, Son SH, Lee K, Jung YW, Lee KY, et al. (October 2017). "Synthesis and biological evaluation of peptide-derived TSLP inhibitors". Bioorganic & Medicinal Chemistry Letters. 27 (20): 4710–4713. doi:10.1016/j.bmcl.2017.09.010. PMID   28927768.
  21. Park BB, Choi JW, Park D, Choi D, Paek J, Kim HJ, et al. (June 2019). "Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors". Scientific Reports. 9 (1): 8762. Bibcode:2019NatSR...9.8762P. doi:10.1038/s41598-019-44853-5. PMC   6584507 . PMID   31217492.
  22. Van Rompaey D, Verstraete K, Peelman F, Savvides SN, Augustyns K, Van Der Veken P, De Winter H (December 2017). "Virtual screening for inhibitors of the human TSLP:TSLPR interaction". Scientific Reports. 7 (1): 17211. Bibcode:2017NatSR...717211V. doi:10.1038/s41598-017-17620-7. PMC   5722893 . PMID   29222519.

Further reading