Nuclear bone morphogenetic protein 2 (nBMP2) is a nuclear variant of the secreted growth factor BMP2. Experiments in nBmp2NLStm mutant mice, which lack nBMP2 in the nucleus, have shown that nBMP2 affects intracellular calcium transport in skeletal muscle and hippocampal neurons. The objective of this study was to determine whether nBMP2 affects the immune system, since activation of lymphocytes and other immune cells depends on intracellular calcium transport. We found that spleens in nBmp2NLStm mutant mice were 24% smaller than in wild type mice. The white pulp of the spleen contains many immune cells, particularly B and T lymphocytes and reduced spleen size in the nBmp2NLStm mutant mice could be caused by a reduced number of lymphocytes migrating to the spleen. When mutants and wild types were challenged with an intravenous infection of 10^7 CFU of S. aureus, they showed similar immune responses. Samples of blood, liver, spleen, kidney and lymph nodes cultured three days after infection showed no difference in post infection bacterial load between mutant and wild type. Likewise, post-infection weight loss and percent survival were similar between mutant and wild type, suggesting that the innate immune response is functional in nBmp2NLStm mice. However, when mice were challenged with a secondary infection, immune response and spleen function were severely impaired. Mutant mice showed higher levels of bacteria remaining in the blood and had lower rate of survival to day 3 after secondary infection. In addition, CD4+ and CD8+ T-cell levels within mutant lymph nodes were significantly reduced, indicating that nBMP2 is involved in the secondary immune response.