Recent studies have hinted that there may be a relationship between p53 end the immune response. In preliminary experiments, we found significantly decreased levels of immunoglobulin deposition in 13 of 16 p53-null tumors compared with 2 of 17 tumors derived from p53(+/-) mice. We further explored the effect of p53 on B-cell development and function. p53-null mice contained more splenic white pulp end more immature B cells in the bone marrow compared with p53(+/-) mice. p53-null B cells were hyperresponsive to proliferative challenge but were not more resistant to signal-induced apoptosis. Several p53 DNA-binding sites were localized to the regulatory regions of immunoglobulin heavy and light chain genes, including the KII site, which serves as an enhancer for rearrangement of the mouse κ chain J cluster genes. Levels of p53 protein and the κ chain sterile transcript increased after exposure of pre-B cells to the DNA damaging agents etoposide and Adriamycin. Our observations suggest that p53 may be involved in B-call maturation and may relay certain stress signals to affect B-cell function.