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A negative feedback loop mediated by the Bcl6-cullin 3 complex limits Tfh cell differentiation.

Rebecca Mathew1, Ai-ping Mao1, Andrew H Chiang2

  • 1Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637Committee on Immunology, Department of Pathology, Howard Hughes Medical Institute, and Department of Chemistry, University of Chicago, Chicago, IL 60637.

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Bcl6-Cul3 complexes regulate T follicular helper (Tfh) cell differentiation. This study reveals Bcl6-Cul3 complexes provide negative feedback during T cell development and activation, restraining excessive Tfh responses.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Biology

Background:

  • Bcl6 (B cell lymphoma 6) is crucial for T follicular helper (Tfh) cell differentiation.
  • Bcl6 is transiently expressed during the CD4(+)CD8(+) double-positive (DP) stage of T cell development.
  • Cullin 3 (Cul3), an E3 ligase, is identified as a novel binding partner of Bcl6.

Purpose of the Study:

  • To investigate the role of Bcl6-Cul3 complexes in T cell development and Tfh cell responses.
  • To elucidate the regulatory mechanisms of Tfh cell differentiation and activation.
  • To understand the negative feedback regulation of Tfh responses.

Main Methods:

  • DP stage-specific deletion of Cul3 or Bcl6 in mice.
  • Analysis of Bcl6 target gene expression (Batf, Bcl6) and epigenetic modifications.
  • Assessment of Tfh cell responses upon antigen encounter in vivo.
  • Ablation of Cul3 in mature CD4(+) splenocytes.

Main Results:

  • DP stage-specific deletion of Cul3 or Bcl6 led to derepression of Batf and Bcl6 in thymocytes.
  • These thymocytes showed increased basal Batf and Bcl6 expression and exaggerated Tfh responses upon antigen encounter.
  • Ablation of Cul3 in mature CD4(+) splenocytes also resulted in exaggerated Tfh responses.
  • Bcl6-Cul3 complexes were found to ubiquitinate histone proteins.

Conclusions:

  • Bcl6-Cul3 complexes play a critical role in negative feedback regulation during T cell development and activation.
  • These complexes restrain excessive Tfh cell responses.
  • The findings reveal a novel function of Bcl6 beyond its role in inducing Tfh responses.