title: Functional characterization of human T cell hyporesponsiveness induced by CTLA4-Ig.
abstract: During activation, T cells integrate multiple signals from APCs and cytokine milieu. The blockade of these signals can have clinical benefits as exemplified by CTLA4-Ig, which blocks interaction of B7 co-stimulatory molecules on APCs with CD28 on T cells. Variants of CTLA4-Ig, abatacept and belatacept are FDA approved as immunosuppressive agents in arthritis and transplantation, yet murine studies suggested that CTLA4-Ig could be beneficial in a number of other diseases. However, detailed analysis of human CD4 cell hyporesponsivness induced by CTLA4-Ig has not been performed. Herein, we established a model to study the effect of CTLA4-Ig on the activation of human naïve T cells in a human mixed lymphocytes system. Comparison of human CD4 cells activated in the presence or absence of CTLA4-Ig showed that co-stimulation blockade during TCR activation does not affect NFAT signaling but results in decreased activation of NF-κB and AP-1 transcription factors followed by a profound decrease in proliferation and cytokine production. The resulting T cells become hyporesponsive to secondary activation and, although capable of receiving TCR signals, fail to proliferate or produce cytokines, demonstrating properties of anergic cells. However, unlike some models of T cell anergy, these cells did not possess increased levels of the TCR signaling inhibitor CBLB. Rather, the CTLA4-Ig-induced hyporesponsiveness was associated with an elevated level of p27kip1 cyclin-dependent kinase inhibitor.
authors: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Yrina
authors: Y
authors: Rochman
authors: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Masashi
authors: M
authors: Yukawa
authors: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Andrey V
authors: AV
authors: Kartashov
authors: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America; Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Artem
authors: A
authors: Barski
mesh_terms: D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology*; D017635:Clonal Anergy; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D060908:CTLA-4 Antigen; D016207:Cytokines; D007136:Immunoglobulins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044767:Ubiquitin-Protein Ligases