title: Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients.
abstract: A substantial proportion of long-term kidney graft recipients, including those with a stable renal function in the absence of immunosuppressive therapy, present a skewed T cell receptor (TCR) Vbeta chain usage, essentially in the CD8+ subset. This study analyzed in more detail phenotypical and functional alterations of CD8+ lymphocytes in drug-free tolerant patients (DF-Tol) compared with recipients with chronic rejection (CR). Phenotyping revealed a significant increase in central memory and a decrease in effector CD8+ lymphocytes in DF-Tol versus CR. The expression of CD28+ and CD27+ on these effector cells was significantly decreased in CR. These profiles were stable over time and independent of treatment. Functionally, the CD8+CD28- lymphocytes were less sensitive to apoptosis than their CD8+CD28+ counterparts, without differences in polyclonal proliferation. The CD8+CD28- cells did not express GITR and FoxP3 but were characterized by high levels of preformed perforin and granzyme A, pointing toward a cytotoxic rather than a suppressor function. CD8+CD28- lymphocytes did not show antigen-specific degranulation when co-cultured with targets that bear donor HLA class I antigens, suggesting that the cytotoxicity is directed either to other determinants of the graft or to nongraft epitopes. Of interest, CD8+ cells from DF-Tol displayed the same profile as healthy individuals, indicating an increase in CD8+CD28- effector lymphocytes in CR rather than a decrease in DF-Tol. CD8+ lymphocytes from stable kidney recipients under conventional maintenance immunosuppression displayed a mixed profile, independent of treatment and time of sampling. Taken collectively, these data show a strong cytotoxicity-associated CD8+CD28- signature in CR and suggest a suppression of pathologic cytotoxicity in DF-Tol. Further prospective studies should assess whether serial CD8+ phenotyping may help to identify patients who are at risk for CR when immunosuppression is tapered.
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale (INSERM), Unité 643: "Immunointervention dans les Allo- et Xénotransplantations," and Institut de Transplantation Et de Recherche en Transplantation (ITERT), Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baeten
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Louis
authors.forename: Christophe
authors.initials: C
authors.lastname: Braud
authors.forename: Cécile
authors.initials: C
authors.lastname: Braudeau
authors.forename: Caroline
authors.initials: C
authors.lastname: Ballet
authors.forename: Frédéric
authors.initials: F
authors.lastname: Moizant
authors.forename: Annaik
authors.initials: A
authors.lastname: Pallier
authors.forename: Magali
authors.initials: M
authors.lastname: Giral
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D018106:CD28 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D018106:CD28 Antigens