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Given the importance of B lymphocytes in inflammation and immune defense against pathogens, mice transgenic for Cre under the control of <i>Cd19</i> promoter (<i>Cd19^Cre/+</i> mice) have been widely used to specifically investigate the role of <i>loxP</i>-flanked genes in B cell development/function. However, impacts of expression/insertion of the Cre transgene on the phenotype and function of B cells have not been carefully studied. Here, we show that the number of marginal zone B and B1a cells was selectively reduced in <i>Cd19^Cre/+</i> mice, while B cell development in the bone marrow and total numbers of peripheral B cells were comparable between <i>Cd19^Cre/+</i> and wild type C57BL/6 mice. Notably, humoral responses to both T cell-dependent and independent antigens were significantly increased in <i>Cd19^Cre/+</i> mice. We speculate that these differences are mainly attributable to reduced surface CD19 levels caused by integration of the Cre-expressing cassette that inactivates one <i>Cd19</i> allele. Moreover, our literature survey showed that expression of <i>Cd19^Cre/+</i> alone may affect the development/progression of inflammatory and anti-infectious responses. Thus, our results have important implications for the design and interpretation of results on gene functions specifically targeted in B cells in the <i>Cd19^Cre/+</i> mouse strain, for instance, in the context of (auto) inflammatory/infectious diseases.