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.
TSLP is produced mainly by non-hematopoietic cells such as fibroblasts, epithelial cells and different types of stromal or stromal-like cells.[ citation needed ]
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]
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]
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]
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.
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 ]
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]
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]
A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's 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 adaptive immune systems.
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Hassall's corpuscles (or thymic corpuscles (bodies)) are structures found in the medulla of the human thymus, formed from eosinophilic type VI epithelial reticular cells arranged concentrically. These concentric corpuscles are composed of a central mass, consisting of one or more granular cells, and of a capsule formed of epithelioid cells. They vary in size with diameters from 20 to more than 100μm, and tend to grow larger with age. They can be spherical or ovoid and their epithelial cells contain keratohyalin and bundles of cytoplasmic fibres. Later studies indicate that Hassall's corpuscles differentiate from medullary thymic epithelial cells after they lose autoimmune regulator (AIRE) expression. This makes them an example of Thymic mimetic cells. They are named for Arthur Hill Hassall, who discovered them in 1846.
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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.
Thymus stromal cells are subsets of specialized cells located in different areas of the thymus. They include all non-T-lineage cells, such as thymic epithelial cells (TECs), endothelial cells, mesenchymal cells, dendritic cells, and B lymphocytes, and provide signals essential for thymocyte development and the homeostasis of the thymic stroma.