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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4609-4616.
Prepublished online as a Blood First Edition Paper on September 2, 2008; DOI 10.1182/blood-2008-03-146241.
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IMMUNOBIOLOGY
Expanded cells in monoclonal TCR- β+/CD4+/NKa+/CD8–/+dim T-LGL lymphocytosis recognize hCMV antigens
Arancha Rodríguez-Caballero1,2,
Andrés C. García-Montero1,2,
Paloma Bárcena1,2,
Julia Almeida1,2,
Francisco Ruiz-Cabello3,
Maria Dolores Tabernero4,
Pilar Garrido5,
Santiago Muñoz-Criado6,
Yorick Sandberg7,
Anton W. Langerak7,
Marcos González8,
Ana Balanzategui8, and
Alberto Orfao1,2
1 Servicio de Citometría & Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain;
2 Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer/Universidad de Salamanca/Consejo Superior Investigaciones Cientificas, Salamanca, Spain;
3 Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Granada, Spain;
4 Unidad de Investigación, Instituto Estudios Ciencias de la Salaud de Castilla y Leon-Hospital Universitario de Salamanca, Salamanca, Spain;
5 Servicio de Hematología, Hospital Universitario Virgen de las Nieves, Granada, Spain;
6 Servicio de Microbiología, Hospital Universitario de Salamanca, Salamanca, Spain;
7 Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; and
8 Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of monoclonal T-cell receptor (TCR)– β+/CD4+/NKa+/CD8–/+dim T-large granular lymphocyte (LGL) lymphocytosis. Because healthy persons show (oligo)clonal expansions of human cytomegalovirus (hCMV)–specific TCRVβ+/CD4+/cytotoxic/memory T cells, we investigate the potential involvement of hCMV in the origin and/or expansion of monoclonal CD4+ T-LGL. Peripheral blood samples from patients with monoclonal TCR-β+/CD4+ T-LGL lymphocytosis and other T-chronic lymphoproliferative disorders were evaluated for the specific functional response against hCMV and hEBV whole lysates as well as the "MQLIPDDYSNTHSTRYVTVK" hCMV peptide, which is specifically loaded in HLA-DRB1*0701 molecules. A detailed characterization of those genes that underwent changes in T-LGL cells responding to hCMV was performed by microarray gene expression profile analysis. Patients with TCR-β+/CD4+ T-LGL displayed a strong and characteristic hCMV-specific functional response, reproduced by the hCMV peptide in a subset of HLA-DRB1*0701+ patients bearing TCRVβ13.1+ clonal T cells. Gene expression profile showed that the hCMV-induced response affects genes involved in inflammatory and immune responses, cell cycle progression, resistance to apoptosis, and genetic instability. This is the first study providing evidence for the involvement of hCMV in the ontogeny of CD4+ T-LGL, emerging as a model disorder to determine the potential implications of quite a focused CD4+/cytotoxic immune response.
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