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/β+ CD4–CD8– Double-Negative T Cells in Patients with Autoimmune Lymphoproliferative Syndrome Express Restricted Vβ TCR Diversity and Are Clonally Related to CD8+ T Cells1
* Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Institut Pasteur, Paris;
Institut National de la Santé et de la Recherche Médicale U668, Paris;
Institut National de la Santé et de la Recherche Médicale U768, Université René Descartes-Paris 5, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris; and
Unité Mixte de Recherche Institut National de la Santé et de la Recherche Médicale U866, IFR-100 University of Burgundy, Centre Hospitalier de l’Université, Dijon, France
The peripheral expansion of 
/β+-CD4–CD8– double negative (DN) T cells in patients with autoimmune lymphoproliferative syndrome (ALPS) is a consistent feature of this disease, and part of the diagnostic criteria of ALPS. The origin of these cells remains undetermined. They could derive from mature T cells that have lost coreceptor expression, or represent a special minor cell lineage. To investigate relationship of DN and single positive (SP) T cells in ALPS, we used Immunoscope technology to analyze the TCRVβ repertoire diversity of sorted DN and SP T cells, and we performed CDR3 sequence analyses of matching clonotypes. We show that DN T cells express all the Vβ gene families that are used by their SP counterparts, though they dominantly use some Vβ genes. Analysis of CDR3 length distribution revealed a diverse polyclonal TCR repertoire for sorted CD4+ T cells, whereas both DN and CD8+ T cells showed a skewed TCR repertoire with oligoclonal expansions throughout most of the Vβ families. CDR3 sequencing of matching clonotypes revealed a significant sharing of CDR3 sequences from selected Vβ-Jβ transcripts between DN and CD8+ T cells. Altogether, these data strongly argue for a CD8 origin of DN T cells in ALPS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Institutional grants from Institut Pasteur and Institut National de la Santé et de la Recherche Médicale, grants from the Agence Nationale de la Recherche (ANR no. 05-MRAR-017), the Association pour la Recherche contre le Cancer, la Ligue Nationale contre le Cancer, la Ligue Parisienne contre le Cancer, and the European Union (6th FP STREP Autorome Consortium, "From Immune Responses in Rare Autoimmune Diseases to Novel Therapeutic Intervention Strategies", LSHM-CT-2004-005264). A.B.-L. was supported by a European Union Autorome post-doctoral grant, V.M. was supported by a post-doctoral fellowship from European Molecular Biology Organization, and A.M.-C. was supported by a post-doctoral fellowship from Association pour la Recherche Contre le Cancer.
2 Address correspondence and reprint requests to Dr. Marie-Lise Gougeon, Antiviral Immunity, Biotherapy and Vaccine Unit, Institut Pasteur, 25-28 rue du Dr. Roux, 75725 Paris Cedex 15, France. E-mail address: mlgougeo{at}pasteur.fr
3 Abbreviations used in this paper: ALPS, autoimmune lymphoproliferative syndrome; DN, double negative; SP, single positive.
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  J. C. Crispin and G. C. Tsokos Human TCR-{alpha}{beta}+ CD4- CD8- T Cells Can Derive from CD8+ T Cells and Display an Inflammatory Effector Phenotype J. Immunol., October 1, 2009; 183(7): 4675 - 4681. [Abstract] [Full Text] [PDF]
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