As the name suggests, TSLP was initially discovered as a growth factor derived from thesupernatant of amousethymicstromalcell line that was found to promote thesurvival and proliferation ofB lymphocytes.[10] In contrast, human TSLP was found to preferentially stimulate myeloid cells.[11]
TSLP was initially observed to have bothpro-inflammatory andanti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the twotranscript variants, with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory.[5][15]
As mentioned, TSLP serves as an alarmin following TLR binding by certainpathogen-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.[21]
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.[21]
TSLP expression is linked to many disease states including asthma,[26] inflammatory arthritis,[27] atopic dermatitis,[28] eczema, eosinophilic esophagitis and other allergic states.[29][30] The factors inducing the activation of TSLP release are not clearly defined.
Expression of TSLP is enhanced underasthma-like conditions (akaAirway HyperResponsiveness or AHR model in the mouse), conditioningAPCs in order to orient the differentiation of T cells coming into the lungs towards aTH2 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 theepidermis induce the production ofpro-inflammatory cytokines likeTNF-alpha by T cells potentially causingatopic dermatitis.[28] 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.[31]
The TSLP signaling axis is an attractive therapeutic target. Amgen'sTezepelumab, a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma.[32][33] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed.[24] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface,[34] natural products[35] and computational fragment-based screening.[36]
^Friend SL, Hosier S, Nelson A, Foxworthe D, Williams DE, Farr A (March 1994). "A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells".Experimental Hematology.22 (3):321–328.PMID8112430.
^abcReche 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):336–343.doi:10.4049/jimmunol.167.1.336.PMID11418668.
^Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, et al. (August 2001). "Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation".Leukemia.15 (8):1286–1292.doi:10.1038/sj.leu.2402175.PMID11480573.S2CID12658276.
^abcHarada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, et al. (March 2009). "Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells".American Journal of Respiratory Cell and Molecular Biology.40 (3):368–374.doi:10.1165/rcmb.2008-0041OC.PMID18787178.
^Saluja R, Zoltowska A, Ketelaar ME, Nilsson G (May 2016). "IL-33 and Thymic Stromal Lymphopoietin in mast cell functions".European Journal of Pharmacology. Pharmacological modulation of Mast cells and Basophils.778:68–76.doi:10.1016/j.ejphar.2015.04.047.PMID26051792.
^abEbner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, et al. (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.PMID17320941.
^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):325–333.doi:10.1007/s00281-003-0152-0.PMID14999427.S2CID9713181.
^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".Nature Immunology.3 (7):673–680.doi:10.1038/ni805.PMID12055625.S2CID9648786.
^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.PMID28927768.
