title: Distinct profiles of cytotoxic granules in memory CD8 T cells correlate with function, differentiation stage, and antigen exposure.
abstract: Cytotoxic CD8 T cells exert their antiviral and antitumor activity primarily through the secretion of cytotoxic granules. Degranulation activity and cytotoxic granules (perforin plus granzymes) generally define CD8 T cells with cytotoxic function. In this study, we have investigated the expression of granzyme K (GrmK) in comparison to that of GrmA, GrmB, and perforin. The expression of the cytotoxic granules was assessed in virus-specific CD8 T cells specific to influenza virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus type 1 (HIV-1). We observed a dichotomy between GrmK and perforin expression in virus-specific CD8 T cells. The profile in influenza virus-specific CD8 T cells was perforin(-) GrmB(-) GrmA(+/-) GrmK(+); in CMV-specific cells, it was perforin(+) GrmB(+) GrmA(+) GrmK(-/+); and in EBV- and HIV-1-specific cells, it was perforin(-/+) GrmB(+) GrmA(+) GrmK(+). On the basis of the delineation of memory and effector CD8 T cells with CD45RA and CD127, the GrmK(+) profile was associated with early-stage memory CD8 T-cell differentiation, the perforin(+) GrmB(+) GrmA(+) profile with advanced-stage differentiation, and the GrmB(+) GrmA(+) Grmk(+) profile with intermediate-stage differentiation. Furthermore, perforin and GrmB but not GrmA and GrmK correlated with cytotoxic activity. Finally, changes in antigen exposure in vitro and in vivo during primary HIV-1 infection and vaccination modulated cytotoxic granule profiles. These results advance our understanding of the relationship between distinct profiles of cytotoxic granules in memory CD8 T cells and function, differentiation stage, and antigen exposure.
authors.affiliation: Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Harari
authors.forename: Felicitas
authors.initials: F
authors.lastname: Bellutti Enders
authors.forename: Cristina
authors.initials: C
authors.lastname: Cellerai
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Bart
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D003587:Cytomegalovirus / Q000276:immunology; D003594:Cytoplasmic Granules / Q000276:immunology*; D053804:Granzymes / Q000096:biosynthesis; D015497:HIV-1 / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D009975:Orthomyxoviridae / Q000276:immunology; D054353:Perforin / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology
chemical_list: D053699:Interleukin-7 Receptor alpha Subunit; D054353:Perforin; D017493:Leukocyte Common Antigens; C088546:GZMK protein, human; D053804:Granzymes