Thymic stromal lymphopoietin (TSLP) is a protein belonging to the

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

family. It is known to play an important role in the maturation of

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

populations through activation of

antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...

s. TSLP is produced mainly by non-

hematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...

cells such as

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

and different types of stromal or stromal-like cells.

Gene ontology

TSLP production has been observed in various species, including humans and mice. In humans TSLP is encoded by the ''TSLP''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

of this gene results in two transcript variants.

Function

It mainly impacts myeloid cells and induces the release of

-attracting chemokines from

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...

s and enhances the maturation of

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + ''-oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue of, ...

(CD11c⁺) dendritic cells. TSLP has also been shown to activate the maturation of a specific subset of dendritic cells located within the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...

, called

Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the ...

s. Within the

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

TSLP activation of both myeloid and

plasmacytoid Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substa ...

(CD123⁺) dendritic cells results in the production of

regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...

Signaling

TSLP signals through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor

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, STA ...

and the IL-7R alpha chain. After binding

STAT5 Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the prote ...

phosphorylation is induced, resulting in the expression of downstream

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...

Disease

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

Asthma

Expression of TSLP is enhanced under

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

-like conditions (aka

Airway HyperResponsiveness Bronchial hyperresponsiveness (or other combinations with airway or hyperreactivity, BH used as a general abbreviation) is a state characterised by easily triggered bronchospasm (contraction of the bronchioles or small airways). Bronchial hyperresp ...

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). The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways.

Inflammatory arthritis

Atopic dermatitis

TSLP-activated Langerhans cells of the

induce the production of

pro-inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include in ...

s like

TNF-alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

by T cells potentially causing

atopic dermatitis Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin (dermatitis). It results in puritis, itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens o ...

. 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.

Inhibition

The TSLP signaling axis is an attractive therapeutic target. Amgen's

Tezepelumab Tezepelumab, sold under the brand name Tezspire, is a human monoclonal antibody used for the treatment of asthma. Tezepelumab blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine that has been suggested to be critical in the initiat ...

, a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma. Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed. Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface, natural products and computational fragment-based screening.

References

External links

* {{Cytokine receptor modulators Immunology