No fully protective vaccine has yet been developed for any human parasite. We previously reported that South American strains of Toxoplasma gondii are adept at immune evasion and cause lethal secondary infections in chronically infected mice. Here we report that unlike susceptible C57BL/6J mice, A/J mice were highly resistant to secondary infection. Mapping immunity loci that segregated within a recombinant inbred panel of mice we identified Nfkbid, a nuclear regulator of NF-κB that is required

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... for B-1 cell development. Nfkbid-null mice (bumble) were susceptible to secondary, but not primary infections and failed to generate parasite-specific IgM and lacked robust parasite-specific IgG. In resistant mice, B-1 cells bore evidence for Nfkbid-dependent responses, including Ighg expression, and were partially responsible for the immunity defect in bumble mice. We propose a model where adaptive immunity to T. gondii must be ′layered′ with B-1 responses to promote protection to virulent challenge.