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1 mars 2017 3 01 /03 /mars /2017 08:16

Définition de l'action des lymphocytes T CD8 + qui induisent l'éclatement prolifératif après la thérapie PD-1.

Im SJ, et al. nature. 2016.

Les infections virales chroniques sont caractérisées par un état de dysfonctionnement des lymphocytes T CD8 (+) associées à l'expression du récepteur inhibiteur de la mort cellulaire programmée 1 (PD-1).

Une meilleure compréhension des mécanismes qui régulent les réponses des lymphocytes T CD8 (+) pendant une infection chronique est nécessaire pour améliorer les immunothérapies qui rétablissent la fonction dans les lymphocytes T CD8 (+) épuisés.

Ici, nous identifions une population de lymphocytes T CD8 (+) spécifiques de virus qui prolifèrent après le blocage de la voie inhibitrice de PD-1 chez des souris chroniquement infectées par le virus de la chorioméningite lymphocytaire (LCMV).

Ces cellules T CD8 (+) spécifiques de LCMV exprimaient le récepteur inhibiteur de PD-1, mais exprimaient également plusieurs molécules co-stimulatrices telles que ICOS et CD28.

Ce sous-ensemble de lymphocytes T CD8 (+) a été caractérisé par une signature de gène unique qui était liée à celle des cellules CD4 (+) T auxiliaires folliculaires (TFH), aux précurseurs de cellules CD8 (+) T et aux progéniteurs de cellules souches hématopoïétiques, et était différent de celle des cellules CD4 (+) TH1 et des effecteurs terminaux CD8 (+).

Cette population de lymphocytes T CD8 (+) a été trouvée seulement dans les tissus lymphoïdes et a résidé principalement dans les zones de cellules T avec des cellules T CD8 (+) naïves.

Ces cellules T CD8 (+) PD-1 ressemblaient à des cellules souches au cours d'une infection chronique par LCMV, subissant un auto-renouvellement et se différenciant également en cellules T CD8 (+) épuisées qui étaient présentes dans les tissus lymphoïdes et non lymphoïdes.

L'éclatement prolifératif après le blocage PD-1 provenait presque exclusivement de ce sous-ensemble de lymphocytes T CD8 (+).

Notamment, le facteur de transcription TCF1 avait un rôle cellulaire intrinsèque et essentiel dans la génération de ce sous-ensemble de lymphocytes T CD8 (+).

Ces résultats permettent une meilleure compréhension de l'épuisement des lymphocytes T et ont des implications dans l'optimisation de l'immunothérapie dirigée contre la PD-1 dans les infections chroniques et le cancer.

PMID 27501248 [PubMed - indexé pour MEDLINE] PMCID PMC5297183 [Disponible le 2017-03-15]

Article intégral : http://www.nature.com/nature/journal/v537/n7620/full/nature19330.html

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Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943–952 (2004) CASISIPubMedArticle Author information Accession codes• References• Author information• Extended data figures and tables Affiliations Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA Se Jin Im, Masao Hashimoto, Junghwa Lee, Haydn T. Kissick, J. Scott Hale, Judong Lee, Tahseen H. Nasti & Rafi Ahmed Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0421, USA Michael Y. Gerner & Ronald N. Germain Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98109, USA Michael Y. Gerner Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA Haydn T. Kissick School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508, Brazil Matheus C. Burger & Helder I. Nakaya Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA Qiang Shan & Hai-Hui Xue Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts 02115, USA Arlene H. Sharpe Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA Arlene H. Sharpe Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA Gordon J. Freeman Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA Hai-Hui Xue Contributions R.A., S.J.I., and J.S.H. designed and analysed the experiments. S.J.I., M.H., Jun.L., Jud.L. and T.H.N. performed experiments. S.J.I., H.T.K., M.C.B. and H.I.N. analysed microarray data. M.Y.G. performed immunofluorescence staining and M.Y.G. and R.N.G. analysed data. Q.S., H.-H.X., A.H.S., and G.J.F. contributed critical materials. R.A. and S.J.I. wrote the manuscript, with all authors contributing to writing and providing feedback. Competing financial interests R.A., A.H.S. and G.J.F. hold patents and receive patent royalties related to the PD-1 inhibitory pathway. R.A., A.H.S. and G.J.F. declare no additional financial interests. The remaining authors declare no competing financial interests. Corresponding author Correspondence to: Rafi Ahmed The microarray data are available in the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE84105.

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