title: Differential CTLA-4 expression in human CD4+ versus CD8+ T cells is associated with increased NFAT1 and inhibition of CD4+ proliferation.
abstract: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a costimulatory molecule that negatively regulates T-cell activation. Originally identified in murine CD8(+) T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells. Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8(+) vs CD4(+) human T cells is unclear. Here, we analyzed CTLA-4 in normal human CD4(+) and CD8(+) T-cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4(+) T cells than in CD8(+) T cells. CTLA-4 is higher at the protein and the transcriptional levels in CD4(+) T cells. This increase is due to the activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4(+) T cells permits greater proliferation in CD4(+) vs CD8(+) cells. These findings demonstrate a differential regulation of CTLA-4 on CD4(+) and CD8(+) T-cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response.
authors.affiliation: Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: D V
authors.initials: DV
authors.lastname: Chan
authors.affiliation: 1] Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA [2] Department of Dermatology and Immunology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Gibson
authors.affiliation: Department of Dermatology and Immunology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Aufiero
authors.affiliation: Department of Dermatology and Immunology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wilson
authors.affiliation: Department of Dermatology and Immunology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Hafner
authors.affiliation: Department of Dermatology and Immunology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Q-S
authors.initials: QS
authors.lastname: Mi
authors.affiliation: 1] Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA [2] Department of Dermatology and Immunology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Wong
mesh_terms: D000107:Acetylation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D060908:CTLA-4 Antigen; D006657:Histones; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human