T-bet regulates IgG class switching and pathogenic autoantibody production

Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5545-50. doi: 10.1073/pnas.082114899.

Abstract

A molecular understanding of the regulation of IgG class switching to IL-4-independent isotypes, particularly to IgG2a, remains largely unknown. The T-box transcription factor T-bet directly regulates Th1 lineage commitment by CD4 T cells, but its role in B lymphocytes has been largely unexplored. We show here a role for T-bet in the regulation of IgG class switching, especially to IgG2a. T-bet-deficient B lymphocytes demonstrate impaired production of IgG2a, IgG2b, and IgG3 and, most strikingly, are unable to generate germ-line or postswitch IgG2a transcripts in response to IFN-gamma. Conversely, enforced expression of T-bet initiates IgG2a switching in cell lines and primary cells. This function contributes critically to the pathogenesis of murine lupus, where the absence of T-bet strikingly reduces B cell-dependent manifestations, including autoantibody production, hypergammaglobulinemia, and immune-complex renal disease and, in particular, abrogates IFN-gamma-mediated IgG2a production. Classical T cell manifestations persisted, including lymphadenopathy and cellular infiltrates of skin and liver. These results identify T-bet as a selective transducer of IFN-gamma-mediated IgG2a class switching in B cells and emphasize the importance of this regulation in the pathogenesis of humorally mediated autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoantibodies / chemistry*
  • Autoimmunity / physiology*
  • B-Lymphocytes / metabolism
  • CD4 Antigens / chemistry
  • CD4-Positive T-Lymphocytes / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Immunoglobulin Class Switching*
  • Immunoglobulin G / chemistry*
  • Interferon-gamma / metabolism
  • Interleukin-4 / metabolism*
  • Lupus Vulgaris / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Plasmids / metabolism
  • Polymerase Chain Reaction
  • RNA, Messenger / metabolism
  • T-Box Domain Proteins
  • T-Lymphocytes / metabolism
  • T-bet Transcription Factor
  • Time Factors
  • Transcription Factors / immunology
  • Transcription Factors / physiology*
  • Transcription, Genetic

Substances

  • Autoantibodies
  • CD4 Antigens
  • Immunoglobulin G
  • RNA, Messenger
  • T-Box Domain Proteins
  • T-bet Transcription Factor
  • Transcription Factors
  • Interleukin-4
  • Interferon-gamma