Thymic stromal lymphopoietin

Last updated
TSLP
TSLP prot.png
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

85480

53603

Ensembl

ENSG00000145777

ENSMUSG00000024379

UniProt

Q969D9

Q9JIE6

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 an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. [5] [6] It shares a common ancestor with IL-7. [7]

Contents

Originally appreciated for its role in immune cell proliferation and development, and then for its pivotal role in type 2 immune responses, TSLP is now known to be involved in other types of immune responses, autoimmune disease, and certain cancers. [5] [6] [8]

Gene ontology

TSLP production has been observed in numerous species, including humans and mice.

In humans, TSLP is encoded by the TSLP gene. [9] [10] Alternative splicing of TSLP results in two transcript variants, a long form (lfTSLP, or just TSLP [5] ) consisting of 159 amino acid residues, and a short form (sfTSLP) consisting of 63 amino acid residues. These variants use different initiation methionine codons and share a carboxy terminus. [10] [11]

sfTSLP

sfTSLP mRNA is constitutively expressed in normal human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and bronchial smooth muscle cells (BSMC). [11] sfTSLP mRNA expression is not significantly upregulated by inflammation. [5]

TSLP

TSLP mRNA is not constitutively expressed in NHBE and has a low level of constitutive expression in NHLF and BSMC. TSLP mRNA expression is upregulated by certain Toll-like receptor (TLR) ligands such as flagellin and poly(I:C), but not by lipopolysaccharide (LPS) or macrophage-activating lipopeptide 2 (MALP-2). [11]

Discovery

As the name suggests, TSLP was initially discovered as a growth factor derived from the supernatant of a mouse thymic stromal cell line that was found to promote the survival and proliferation of B lymphocytes. [12]

Function

TSLP was initially observed to have both pro-inflammatory and anti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the two transcript variants, with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory. [5] [13]

sfTSLP

sfTSLP inhalation prevents airway epithelial barrier disruption caused by the inhalation of house dust mite (HDM) antigens in mice who had been sensitised to HDM, an asthma-like model. [14] Similarly, sfTSLP reduces the severity of dextran sulphate sodium (DSS)-induced colitis in mice, a model of inflammatory bowel disease (IBD), and prevents endotoxic shock and sepsis resulting from bacterial infections. [13]

Signalling

A receptor for sfTSLP has not been discovered. It is not known whether sfTSLP also signals via the TSLP receptor complex. [15]

TSLP

Epithelium defense

TSLP's pivotal role in initiating immune responses begins with its release by epithelial or stromal cells of the lungs, skin, or gastrointestinal tract as an alarmin following mechanical cell injury, pattern recognition receptor (PRR) and protease-activated receptor (PAR) activation, stimulation by certain cytokines, chemical irritation, or infection. [5]

When local mast cells bind an allergen, they produce TSLP indirectly by releasing tryptase in an FcεRI-dependent manner, activating PARs on epithelial cells and causing them to release TSLP. [16] Unlike IL-33, a similarly acting alarmin, TSLP is usually not constitutively expressed and must be upregulated by transcription factors such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or activator protein (AP)1 following insult. [5] [17]

Type 2 immune responses

Local dendritic cells (DCs) are among the most important targets of TSPL, as they, among other antigen presenting cells (APCs), allow the immune system to mount adaptive responses. TSLP signalling grants DCs the exact phenotype needed to prime naive CD4+ T cells into TH2 pro-inflammatory cells, or producing type 2 cytokines, namely by upregulating OX40L, CD80, and CD86. TSLP-stimulated DCs that migrate into draining lymph nodes can prime CD4+ T cells into follicular helper T (TFH) cells, which in turn can promote immunoglobulin (Ig)G and E production by resident B lymphocytes, thus initiating type 2 immune responses. TH2 can also facilitate B cell class switching towards IgE. [18]

Type 1 and 3 immune responses

As mentioned, TSLP serves as an alarmin following TLR binding by certain pathogen-associated molecular patterns (PAMPs), including viral and bacterial ones, rather than just irritation by allergens. Thus, TSLP also plays an early role in the initiation of type 1 and 3 immune responses to pathogens. This activity has thus far been best described in the respiratory mucosa. [19]

TSLP-activated CD11b+ DCs can promote the proliferation and long-term survival of CD8+ cytotoxic T cells, promoting the development of lasting adaptive cellular immunity. Analogously, TSLP-activated CD11c+ cells are essential for the development of IgA antibodies following pneumococcal infection. TSLP also holds considerable promise as a novel vaccine adjuvant and anti-cancer immunotherapy due to its broad and potent alarmin functionality, as is evidenced by numerous animal studies. [19]

Germinal centre formation

Germinal centres (GCs) are microstructures that form in secondary lymphoid organs during immune responses. GCs are the sites of the clonal expansion of B lymphocytes and the affinity maturation of their antibodies, thus allowing the immune system to generate antibodies with a high affinity for antigens. [20] TSLP may play an important role in the formation of GCs, as the depletion of TSPLR in CD4+ T cells prevented their formation in mice, as well as the generation of IgG1. [21]

Signalling

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 TSLP receptor (TSLPR) and the IL-7Rα chain. Upon binding, Janus kinase (JAK)1 and 2 are activated, leading to the activation of signal transducer and activator of transcription (STAT)5A and 5B and, to a lesser extent, STAT1 and 3. These transcription factors upregulate pro-inflammatory cytokines such as IL-4, 5, 9, and 13. [5] [23]

Disease

TSLP expression is linked to many disease states including asthma, [24] inflammatory arthritis, [25] atopic dermatitis, [26] eczema, eosinophilic esophagitis and other allergic states. [27] [28] 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 ]

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. [26] 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. [29]

Therapeutic targeting

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. [30] [31] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed. [22] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface, [32] natural products [33] and computational fragment-based screening. [34]

Related Research Articles

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Interleukin 33</span> IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines.

Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.

<span class="mw-page-title-main">Interleukin 25</span> 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.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

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.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

<span class="mw-page-title-main">CCL18</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">STAT6</span> Protein and coding gene in humans

Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.

<span class="mw-page-title-main">CCR9</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene. This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">CRLF2</span> Protein-coding gene in humans

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).

<span class="mw-page-title-main">Microbial symbiosis and immunity</span>

Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.

<span class="mw-page-title-main">Mucosal immunology</span> Field of study

Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more.

<span class="mw-page-title-main">IL1RL1</span> Protein-coding gene in the species Homo sapiens

Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.

<span class="mw-page-title-main">ILC2</span>

ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell receptor because of the lack of recombination activating gene. ILC2s produce type 2 cytokines and are involved in responses to helminths, allergens, some viruses, such as influenza virus and cancer.

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.

Type 2 inflammation is a pattern of immune response. Its physiological function is to defend the body against helminths, but a dysregulation of the type 2 inflammatory response has been implicated in the pathophysiology of several diseases.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024379 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  20. ↑ Victora, Gabriel D.; Nussenzweig, Michel C. (2022-04-26). "Germinal Centers". Annual Review of Immunology. 40 (1): 413–442. doi: 10.1146/annurev-immunol-120419-022408 . ISSN   0732-0582. PMID   35113731.
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  25. ↑ 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.
  26. 1 2 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): 982–990. doi:10.1016/j.jaci.2007.01.003. PMID   17320941.
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  34. ↑ 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.
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