ABSTRACTHelicobacter pyloriis the major risk factor for gastric cancer. H. pyloriharboring the type IV secretion system (T4SS) and its effector CagA encoded on the cagpathogenicity Island (cagPAI) increases the risk. H. pyloriPMSS1 has a multi-cagAgenotype, modulating cagAcopy number dynamically from zero to four copies. To examine the effect of the immune response on cagAcopy number change, we utilized a mouse model with different immune status. PMSS1 recovered from Rag1−/−mice, lacking functional T or B cells, retained more cagAcopies. PMSS1 recovered from Il10−/−mice, showing intense inflammation, had fewer cagAcopies compared to those recovered from wild-type mice. Moreover, cagAcopy number of PMSS1 recovered from wild-type and Il10−/−mice was positively correlated with the capacity to induce IL-8 secretion at four weeks of infection. Since recombination in cagYinfluences T4SS function, including CagA translocation and IL-8 induction, we constructed a multiple linear regression model to predict H. pylori-induced IL-8 expression based on cagAcopy number and cagYrecombination status; H. pyloriinduces more IL-8 secretion when the strain has more cagAcopies and intact cagY. This study shows that H. pyloriPMSS1 in mice with less intense immune response possess higher cagAcopy number than those infected in mice with more intense immune response and thus the multi-cagAgenotype, along with cagYrecombination, functions as an immune-sensitive regulator of H. pylorivirulence.