Abstract
Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii, which causes 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. To identify correlates of immunity, we utilized forward genetics to identify Nfkbid, a nuclear regulator of NF-κB that is required for B cell activation and B-1 cell development. Nfkbid-null mice ("bumble") did not generate parasite-specific IgM and lacked robust parasite-specific IgG, which correlated with defects in B-2 cell maturation and class-switch recombination. Though high-affinity antibodies were B-2 derived, transfer of B-1 cells partially rescued the immunity defects observed in bumble mice and were required for 100% vaccine efficacy in bone marrow chimeric mice. Immunity in resistant mice correlated with robust isotype class-switching in both B cell lineages, which can be fine-tuned by Nfkbid gene expression. We propose a model whereby humoral immunity to T. gondii is regulated by Nfkbid and requires B-1 and B-2 cells for full protection.
Highlights
The goal of vaccination is to induce immunological memory that can protect from natural infection challenge
When mice are given a natural infection with a low virulent type III CEP strain and allowed to progress to chronic infection for 35–42 days, the immunological memory that develops is known to protect against secondary infections with the commonly studied lab strain, type I RH
Highly virulent “atypical” strains such as those isolated from South America (VAND, GUY-DOS, GUY-MAT, TgCATBr5) or France (MAS, GPHT, FOU) and the clonal type I GT1 strain led to morbidity and mortality in C57BL/6J mice at varying frequencies, depending on the strain type and their virulence factors [25]
Summary
The goal of vaccination is to induce immunological memory that can protect from natural infection challenge. T. gondii strains differ dramatically in primary infection virulence in laboratory mice [3] and in severity of human toxoplasmosis [4,5,6]. Such infections can be overcome by immunological memory responses elicited by vaccination or natural infection. Memory CD8 T cells and induction of IFNγ are primarily responsible for protection against lethal secondary infections with the widely studied type I RH strain, which has a lethal dose of one parasite in naïve mice [7,8,9]. CD4 T cells are required to help the formation of effector CD8 T cell [10] and B cell responses [11], but the ability to adoptively transfer vaccineelicited cellular immunity to naïve recipients against type I RH challenge is unique to memory CD8 T cells [8,9]
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