title: EBV-specific CD8+ T cells from asymptomatic pediatric thoracic transplant patients carrying chronic high EBV loads display contrasting features: activated phenotype and exhausted function.
abstract: Serial EBV load monitoring of clinically asymptomatic pediatric thoracic organ transplant patients has identified three groups of children who exhibit undetectable (<100 copies/ml), chronic low (100-16,000 copies/ml), or chronic high (>16,000 copies/ml) EBV loads in peripheral blood. Chronic high EBV load patients have a 45% rate of progression to late-onset posttransplant lymphoproliferative disorders. In this article, we report that asymptomatic patients carrying EBV loads (low and high) expressed increased frequencies of EBV-specific CD8(+) T cells, as compared with patients with undetectable EBV loads. Although patients with low viral load displayed EBV-specific CD8(+) T cells with moderate signs of activation (CD38(+/-)/CD127(+/-)), programmed death 1 upregulation and effective IFN-γ secretion, high EBV load carriers showed significant CD38(+) upregulation, features of cellular exhaustion (programmed death 1(+)/CD127(-)) accompanied by a decline in IFN-γ release. Immunopolarization of EBV-specific CD8(+) T cells was skewed from the expected type 1 (IFN-γ) toward type 0 (IFN-γ/IL-5) in patients, and Tr1 (IL-10) in high load carriers. These results indicate the importance of chronic EBV load and of the levels of antigenic pressure in shaping EBV-specific memory CD8(+) T cells. Concomitant phenotypic and functional EBV monitoring is critical for identifying the complex "functional" versus "exhausted" signature of EBV-specific CD8(+) T cells, with implications for immunologic monitoring in the clinic.
authors: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
authors: Camila
authors: C
authors: Macedo
authors: Steven A
authors: SA
authors: Webber
authors: Albert D
authors: AD
authors: Donnenberg
authors: Iulia
authors: I
authors: Popescu
authors: Yun
authors: Y
authors: Hua
authors: Michael
authors: M
authors: Green
authors: David
authors: D
authors: Rowe
authors: Louise
authors: L
authors: Smith
authors: Maria M
authors: MM
authors: Brooks
authors: Diana
authors: D
authors: Metes
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000293:Adolescent; D017209:Apoptosis; D058345:Asymptomatic Infections; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D016027:Heart Transplantation / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D016040:Lung Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000821:virology; D008297:Male; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019562:Viral Load
chemical_list: D015848:Interleukin-5; D053699:Interleukin-7 Receptor alpha Subunit; D016753:Interleukin-10; D007371:Interferon-gamma; D051997:ADP-ribosyl Cyclase 1