Alt. symbols: CD288

Approved name: toll like receptor 8
Alt. names: toll-like receptor 8

Location: Xp22.2: 12906620 - 12923169 (+)
Gene type: protein_coding, 2 transcripts.

Scores: LoFtool: 0.288000 | pLI: 0.93102613 | LOEUF: 0.486

HGNC: 15632

NCBI: 51311, RefSeq: NG_012882.2

Ensembl: ENSG00000101916.12

LRG_ | Status: none

OMIM: 300366

Expression | ProteinAtlas

TLR8 encodes Toll-like receptor 8, an endosomal receptor that plays key roles in innate and adaptive immunity (PMID: 25297876, 32433612) via its sensing of RNA degradation products from pathogens. Specifically, it recognizes GU-rich single-stranded RNA (GU-rich RNA) derived from viruses such as SARS-CoV-2, SARS-CoV-1 and HIV-1 that are initially processed by RNase T2 (PMID: 31778653, 33718825). Agonist binding leads to TLR8 dimerization via its TIR domains and recruitment of downstream adapter MYD88 (PMID: 23520111, 25599397, 26929371, 33718825). Subsequent Myddosome signaling complex formation (involving IRAK4, IRAK1, TRAF6, and TRAF3) leads to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively (PMID: 16737960, 17932028, 29155428).

Hemizygous mutations in TLR8 cause X-linked immunodeficiency-98 with autoinflammation (IMD98) [OMIM:301078], characterized by recurrent infections associated with autoimmune cytopenias, lymphoproliferation and autoinflammation in the first decade of life. Mostly males are affected but carrier females can also have mild symptoms. Labs show evidence of immune dysregulation, including hypogammaglobulinemia with reduced memory B cells, skewed T-cell subsets, activated T cells and monocytes, increase d levels of proinflammatory cytokines. The mutations identified by Aluri et al. (2021) via exome sequencing occurred de novo and notably 5 of 6 patients harbored somatic mosaicism with 8-26% expression in blood cells (PMID: 33512449). In vitro functional studies showed that the mutations resulted in enhanced NF-kappaB activation compared to controls upon TLR8 ligand stimulation, consistent with a gain-of-function effect. Myeloid cells differentiated from patient fibroblast-derived iPSCs also showed increased NF-kappaB signaling and cytokine production in response to TLR8 stimulation relative to wild-type controls. Use of a reporter cell line also expressing TLR7 showed that these effects were specific to TLR8. The authors proposed that the phenotypic variability, including age at onset, seen for their patients may be due to different natural histories of environmental exposure to pathogenic triggers, in addition to genetic factors. More recently, Fejtkova et al. (2022) identified a maternally-inherited hemizygous germline missense mutation (G572V) in a pair of monozygotic twin boys with severe autoimmune hemolytic anemia, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis (PMID: 34981838). Their mother also had a history of polyarthritis and steroid-sensitive antiphospholipid syndrome. One patient responded to treatment with hydroxychloroquine, whereas the other underwent HSCT. Both patient cells and transfected HEK293 cells showed increased NF-kappaB transcriptional activity and proinflammatory cytokine (IL-1beta, IL-6, TNF-alpha) production compared to wildtype. The authors showed that this substitution impaired TLR8 stability and led to cross-reactivity with TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling, resulting in hyperinflammation. [Load More]