A forward genetic screen reveals roles for Nfkbid, Zeb1, and Ruvbl2 in humoral immunity

Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12286-93. doi: 10.1073/pnas.1209134109. Epub 2012 Jul 3.

Abstract

Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair humoral immunity were recovered, and 19 of these mutations have been positionally cloned. Among the phenovariants were bumble, cellophane, and Worker ascribed to mutations in Nfkbid, Zeb1, and Ruvbl2, respectively. We show that IκBNS, the nuclear IκB-like protein encoded by Nfkbid, is required for the development of marginal zone and peritoneal B-1 B cells and additionally required for extrafollicular antibody responses to T-independent and -dependent immunogens. Zeb1 is also required for marginal zone and peritoneal B-1 B-cell development as well as T-cell development, germinal center formation, and memory B-cell responses. Finally, Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses. Collectively, the mutations that we identified give us insight into the points at which disruption of an antibody response can occur. All of the mutations identified to date directly affect lymphocyte development or function; none have an exclusive effect on cells of the innate immune system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Animals
  • B-Lymphocyte Subsets / immunology*
  • Cells, Cultured
  • DNA Helicases / genetics
  • DNA Helicases / immunology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Immunity, Humoral / physiology*
  • Immunity, Innate / physiology
  • Intracellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / immunology*
  • Mice
  • Mice, Knockout
  • Mutation
  • Proteins / genetics
  • Proteins / immunology*
  • T-Lymphocytes / immunology
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Homeodomain Proteins
  • IkappaBNS protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Proteins
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • ATPases Associated with Diverse Cellular Activities
  • DNA Helicases
  • RUVBL2 protein, mouse