title: Expansion of highly differentiated cytotoxic terminally differentiated effector memory CD8+ T cells in a subset of clinically stable kidney transplant recipients: a potential marker for late graft dysfunction.
abstract: Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vβ repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8(+) T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vβ diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA(+)CCR7(-)CD27(-)CD28(-)) CD8(+) T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8(+) T cells to secrete TNF-α and IFN-γ. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8(+) T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8(+) T cells may improve the early identification of at-risk patients.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Michelle
authors.initials: M
authors.lastname: Yap
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Françoise
authors.initials: F
authors.lastname: Boeffard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 940, Paris, France; and.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Clave
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Annaick
authors.initials: A
authors.lastname: Pallier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Richard
authors.initials: R
authors.lastname: Danger
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Magali
authors.initials: M
authors.lastname: Giral
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Jacques
authors.initials: J
authors.lastname: Dantal
authors.affiliation: Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Université de Nantes, Equipe d'Accueil 4275 and Labex Transplantex, Nantes, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Foucher
authors.affiliation: Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France;
authors.forename: Cécile
authors.initials: C
authors.lastname: Guillot-Gueguen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 940, Paris, France; and.
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France; jean-paul.soulillou@univ-nantes.fr.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Nantes, France; Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie-Néphrologie, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Degauque
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016827:CD8 Antigens / Q000097:blood*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D005260:Female; D006084:Graft Rejection / Q000097:blood*; D053804:Granzymes / Q000097:blood; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology; D007371:Interferon-gamma / Q000097:blood; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000601:surgery*; D017493:Leukocyte Common Antigens / Q000097:blood*; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000097:blood; D011446:Prospective Studies; D020825:T-Box Domain Proteins / Q000097:blood; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000098815:T-bet Transcription Factor
chemical_list: D015415:Biomarkers; D016827:CD8 Antigens; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D053804:Granzymes