TLR9 polymorphisms determine murine lymphocyte responses to Helicobacter: results from a genome-wide scan

Immune responses to microorganisms in the gastrointestinal tract must be carefully controlled to avoid disease. Helicobacter are Gram-negative bacteria which cause persistent infection and, in a minority of hosts, peptic ulceration or gastric cancer. Lymphocyte responses are important determinants of the outcome of infection. Therefore, it is important to identify the genetic determinants of lymphocyte responses to this mucosal pathogen. Using a (C57BL/6xBALB/c) F2 mouse model of Helicobacter infection, we mapped a region of linkage for lymphoproliferation to chromosome 9. Analysis of candidate genes in this region revealed variation of DNA sequence and gene expression in the TLR9 gene between C57BL/6 and BALB/c mouse strains. Reporter assays demonstrated higher levels of TLR9 transcriptional activity and increased NF-kappaB activation associated with the C57BL/6 TLR9 promoter and coding sequences. The importance of TLR9 in the control of lymphocyte responses was confirmed by demonstrating that lymphoproliferation and IFN-gamma secretion was diminished in the TLR9-/- mouse. Furthermore, neutrophil infiltration of the gastric epithelium is reduced in the absence of TLR9. Regulation of TLR9 expression and signalling therefore appears to play an important role in the control of lymphocyte responses to Helicobacter and potentially other luminal microorganisms.