Impaired proteasome function activates GATA3 in T cells and upregulates CTLA-4: relevance for Sézary syndrome

J Invest Dermatol. 2013 Jan;133(1):249-57. doi: 10.1038/jid.2012.265. Epub 2012 Sep 6.


Highly regulated expression of the negative costimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) on T cells modulates T-cell activation and proliferation. CTLA-4 is preferentially expressed in Th2 T cells, whose differentiation depends on the transcriptional regulator GATA3. Sézary syndrome (SS) is a T-cell malignancy characterized by Th2 cytokine skewing, impaired T-cell responses, and overexpression of GATA3 and CTLA-4. GATA3 is regulated by phosphorylation and ubiquitination. In SS cells, we detected increased polyubiquitinated proteins and activated GATA3. We hypothesized that proteasome dysfunction in SS T cells may lead to GATA3 and CTLA-4 overexpression. To test this hypothesis, we blocked proteasome function with bortezomib in normal T cells, and observed sustained GATA3 and CTLA-4 upregulation. The increased CTLA-4 was functionally inhibitory in a mixed lymphocyte reaction (MLR). GATA3 directly transactivated the CTLA-4 promoter, and knockdown of GATA3 messenger RNA and protein inhibited CTLA-4 induction mediated by bortezomib. Finally, knockdown of GATA3 in patient's malignant T cells suppressed CTLA-4 expression. Here we demonstrate a new T-cell regulatory pathway that directly links decreased proteasome degradation of GATA3, CTLA-4 upregulation, and inhibition of T-cell responses. We also demonstrate the requirement of the GATA3/CTLA-4 regulatory pathway in fresh neoplastic CD4+ T cells. Targeting of this pathway may be beneficial in SS and other CTLA-4-overexpressing T-cell neoplasms.

Publication types

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

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Boronic Acids / pharmacology
  • Bortezomib
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism*
  • Cells, Cultured
  • Female
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism*
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology
  • Gene Knockdown Techniques
  • Humans
  • Lymphocyte Culture Test, Mixed
  • Male
  • Middle Aged
  • Polyubiquitin
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Pyrazines / pharmacology
  • Sezary Syndrome / genetics
  • Sezary Syndrome / metabolism*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • T-Lymphocytes / metabolism*


  • Antineoplastic Agents
  • Boronic Acids
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Pyrazines
  • Polyubiquitin
  • Bortezomib
  • Proteasome Endopeptidase Complex