Genetic mapping reveals Nfkbid as a central regulator of humoral immunity to Toxoplasma gondii
Abstract
Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity isToxoplasma 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 identifyNfkbid, 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 inbumblemice 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 byNfkbidgene expression. We propose a model whereby humoral immunity toT.gondiiis regulated byNfkbidand requires B-1 and B-2 cells for full protection.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 06, 2021
- Source ID
- 10.1371/journal.ppat.1010081
Entities
People
- Jessica N. Wilson
- Juan Camilo Sánchez-Arcila
- Julia A. Alvarez
- Kirk D C Jensen
- Nicole Baumgarth
- Safuwra Wizzard
- Samantha D. Splitt
- Scott P. Souza
- Zheng Luo
Organizations
- Hellman Foundation
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- United States Department of Defense