CD19 serves as a cell surface response regulator that establishes signaling thresholds critical for B lymphocyte development and activation. B lymphocytes from CD19-deficient mice are hyporesponsive to transmembrane signals, while B lymphocytes from mice that overexpress CD19 to even a small extent (25% increase) become hyperresponsive. The B-1 subpopulation of B lymphocytes is particularly sensitive to CD19 regulation, since their development is severely decreased in CD19-deficient mice. The effect of altered CD19 expression levels on the development of B cells was therefore examined using transgenic mice that express varying levels of cell surface CD19. In this study, immature B cells within the bone marrow of wild-type mice were found to specifically up-regulate CD19 expression levels by twofold as they mature, while CD5+ B cells within the spleen and peritoneum expressed even higher levels of CD19. The development of CD5+ B cells was severely decreased in CD19-deficient mice, while there was a linear correlation between increased CD19 expression levels and the increased frequency of CD5+ B cells within the peritoneum and spleen. In fact, CD5+ B cells became a major B lymphocyte population in mice that overexpressed CD19. Increased expression of CD19 also correlated with increased levels of endogenous anti-DNA Abs and rheumatoid factor. These results indicate that up-regulated expression of CD19 is functionally important for B cell development and that CD19 establishes signaling thresholds that regulate the generation of B-1 lymphocytes as well as the development of autoantibodies.