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 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, epithelial cells and different types of

stromal Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa ...

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.

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 T cell-attracting chemokines from monocytes 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 cells. Within the thymus 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 cells.

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 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.

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-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 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 considere ...

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 cytokines like TNF-alpha 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