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.
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. 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. 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 File:TSLP wiki 5j11.png|thumb|350x350px|Crystal structure of human TSLP in complex with TSLP-R and IL-7Ra (pdb 5j11) == Clinical significance ==