title: Impaired proteasome function activates GATA3 in T cells and upregulates CTLA-4: relevance for Sézary syndrome.
abstract: 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.
authors.affiliation: Division of Dermatology, The Ohio State University, Columbus, OH, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Gibson
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Derek V
authors.initials: DV
authors.lastname: Chan
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Hake
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Henry K
authors.initials: HK
authors.lastname: Wong
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D025821:Polyubiquitin; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D012751:Sezary Syndrome / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D011719:Pyrazines; D025821:Polyubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex