IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1196-E1204. doi: 10.1073/pnas.1621258114. Epub 2017 Jan 30.

Abstract

Class-switch recombination (CSR) alters the Ig isotype to diversify antibody effector functions. IgD CSR is a rare event, and its regulation is poorly understood. We report that deficiency of 53BP1, a DNA damage-response protein, caused age-dependent overproduction of secreted IgD resulting from increased IgD CSR exclusively within B cells of mucosa-associated lymphoid tissues. IgD overproduction was dependent on activation-induced cytidine deaminase, hematopoietic MyD88 expression, and an intact microbiome, against which circulating IgD, but not IgM, was reactive. IgD CSR occurred via both alternative nonhomologous end-joining and homologous recombination pathways. Microbiota-dependent IgD CSR also was detected in nasal-associated lymphoid tissue of WT mice. These results identify a pathway, present in WT mice and hyperactivated in 53BP1-deficient mice, by which microbiota signal via Toll-like receptors to elicit IgD CSR.

Keywords: 53BP1; IgD; Toll-like receptor; class-switch recombination; microbiota.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology
  • Cytidine Deaminase / metabolism
  • DNA End-Joining Repair
  • Female
  • Immunoglobulin Class Switching*
  • Immunoglobulin D / genetics
  • Immunoglobulin D / immunology*
  • Immunoglobulin D / metabolism
  • Lymphoid Tissue / immunology*
  • Lymphoid Tissue / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microbiota / genetics
  • Microbiota / immunology*
  • Mucous Membrane / immunology*
  • Mucous Membrane / metabolism
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism
  • Recombination, Genetic
  • Tumor Suppressor p53-Binding Protein 1 / deficiency
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / immunology

Substances

  • Immunoglobulin D
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • Cytidine Deaminase