Thymic stromal lymphopoietin

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. In contrast, human TSLP was found to preferentially stimulate myeloid cells.

Gene

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

In humans, TSLP is encoded by the TSLP gene. Alternative splicing of TSLP results in two transcript variants, a long form (lfTSLP, or just TSLP) 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.

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

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).

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.

Short form

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. 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.

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

Long form

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.

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. 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.

Local dendritic cells (DCs) are among the most important targets of TSLP, 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.

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.

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.

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. 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.

Signalling

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.

Clinical significance

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 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.

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. 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.

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. 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

References

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