Nfkbid is required for immunity and antibody responses to Toxoplasma gondii

• Published in: bioRxiv
• Main Authors: Souza, Scott P, Splitt, Samantha D, Alvarez, Julia A, Juan Camilo Sánchez-Arcila, Wilson, Jessica, Wizzard, Safuwra, Luo, Zheng, Baumgarth, Nicole, Jensen, Kirk
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.05.2021
• Subjects: B-1 cells; Cell activation; Children; Class switching; Gene expression; Genetic screening; Humoral immunity; Immunoglobulin G; Immunoglobulin M; Inbreeding; Infections; NF-κB protein; Parasites; Parasitic diseases; Pathogens; Protozoa; Recombination; Secondary infection; Toxoplasma gondii; Vaccines
• DOI: 10.1101/2020.06.26.174151

Protective humoral responses are important in generating natural immunity to parasitic infections but have been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii. 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. To identify correlates of immunity, mouse genetics were used to map immunity loci that segregated within a recombinant inbred panel (AxB, BxA). We identified Nfkbid, a nuclear regulator of NF-κB that is required for B cell activation and B-1 cell development. Nfkbid-null mice (bumble) were susceptible to secondary, but not primary infections. Bumble mice 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 are B-2 derived, B-1 cells are absent in bumble mice and transfer of B-1 cells partially rescued the observed immunity defect. In comparison, humoral immunity to T. gondii in resistant A/J 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 where humoral immunity to T. gondii is driven by Nfkbid and must be "layered" by both B-1 and B-2 cells to promote protection to virulent challenge. Competing Interest Statement The authors have declared no competing interest.