Open AccessGenetic mapping reveals Nfkbid as a central regulator of humoral immunity to Toxoplasma gondii
Author(s) -
Scott P. Souza,
Samantha D. Splitt,
Juan Camilo SánchezArcila,
Julia A Alvarez,
Jessica N. Wilson,
Safuwra Wizzard,
Zheng Luo,
Nicole Baumgarth,
Kirk D. C. Jensen
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1010081
Subject(s) - biology , immunity , humoral immunity , toxoplasma gondii , immunoglobulin class switching , virology , immunology , antibody , acquired immune system , immune system , b cell , isotype , monoclonal antibody
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.