B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses

J Immunol. 2015 Apr 1;194(7):3065-78. doi: 10.4049/jimmunol.1401896. Epub 2015 Mar 4.


Class switch DNA recombination (CSR) is central to the maturation of the Ab response because it diversifies Ab effector functions. Like somatic hypermutation, CSR requires activation-induced cytidine deaminase (AID), whose expression is restricted to B cells, as induced by CD40 engagement or dual TLR-BCR engagement (primary CSR-inducing stimuli). By constructing conditional knockout Igh(+/C)γ(1-cre)Rab7(fl/fl) mice, we identified a B cell-intrinsic role for Rab7, a small GTPase involved in intracellular membrane functions, in mediating AID induction and CSR. Igh(+/C)γ(1-cre)Rab7(fl/fl) mice displayed normal B and T cell development and were deficient in Rab7 only in B cells undergoing Igh(C)γ(1-cre) Iγ1-Sγ1-Cγ1-cre transcription, as induced--like Igh germline Iγ1-Sγ1-Cγ1 and Iε-Sε-Cε transcription--by IL-4 in conjunction with a primary CSR-inducing stimulus. These mice could not mount T-independent or T-dependent class-switched IgG1 or IgE responses while maintaining normal IgM levels. Igh(+/C)γ(1-cre)Rab7(fl/fl) B cells showed, in vivo and in vitro, normal proliferation and survival, normal Blimp-1 expression and plasma cell differentiation, as well as intact activation of the noncanonical NF-κB, p38 kinase, and ERK1/2 kinase pathways. They, however, were defective in AID expression and CSR in vivo and in vitro, as induced by CD40 engagement or dual TLR1/2-, TLR4-, TLR7-, or TLR9-BCR engagement. In Igh(+/C)γ(1-cre)Rab7(fl/fl) B cells, CSR was rescued by enforced AID expression. These findings, together with our demonstration that Rab7-mediated canonical NF-κB activation, as critical to AID induction, outline a novel role of Rab7 in signaling pathways that lead to AID expression and CSR, likely by promoting assembly of signaling complexes along intracellular membranes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation*
  • Antibody Specificity / immunology
  • Antigens / immunology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Survival / drug effects
  • Cell Survival / immunology
  • Cytidine Deaminase / genetics*
  • Gene Expression Regulation*
  • Gene Order
  • Genetic Loci
  • Germ Cells / metabolism
  • Immunoglobulin Class Switching*
  • Immunoglobulin E / biosynthesis
  • Immunoglobulin E / genetics
  • Immunoglobulin E / immunology
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin gamma-Chains / genetics
  • Interleukin-4 / metabolism
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transcription, Genetic
  • rab GTP-Binding Proteins / deficiency
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*
  • rab7 GTP-Binding Proteins


  • Antigens
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin gamma-Chains
  • NF-kappa B
  • rab7 GTP-Binding Proteins
  • rab7 GTP-binding proteins, human
  • rab7 GTP-binding proteins, mouse
  • Interleukin-4
  • Immunoglobulin E
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase
  • rab GTP-Binding Proteins