title: Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors.
abstract: We have analyzed the phenotype, cytokine profile, and mitotic history (telomere length) of monoclonal T-cell expansions in 5 CD3(+) T-cell large granular lymphocyte (TLGL) leukemia patients by fluorescence activated cell sorting (FACS) and single-cell polymerase chain reaction (PCR). We confirm that the common phenotype of TLGL leukemia is CD3(+)CD8(+)CD45RA(+)CD27(-)CD94(+)(CD57(+)). Interestingly, the C-type lectin-like type killer cell receptor CD94 was invariably associated with the activating form of its signal-transducing molecule NKG2. Furthermore, when judged by criteria such as interferon gamma (IFN-gamma)/tumor necrosis factor (TNF) production, expression of granzyme, FasL, and NKG2D, the TLGL cells had all the features of a cytotoxic effector T cell. Telomere shortening in TLGL cells was in the normal range for CD8(+) T cells, indicating that they had not divided significantly more than chronically stimulated CD8(+) T cells in healthy individuals. In 25 of 27 controls, cells with a TLGL phenotype occurred at low (1%-3%) frequencies. However, in the other 2 individuals (ages 28-36 years), large stable (> 3 years) monoclonal expansions of CD3(+)CD8(+)CD45RA(+)CD27(-)CD57(+)CD94(+) NKG2C(+) were found which rendered these controls phenotypically indistinguishable from TLGL leukemia patients. We believe that the TLGL clonopathy, rather than being of a neoplastic nature, is more likely an extreme manifestation of the large and stable clonal size characteristic of CD8(+) effector cells. Such a TLGL clone consisting of cells without any particular pathologic trait might exist in a considerable number of individuals. Clinical symptoms may occur in individuals in whom the TLGL clone encounters antigen and is triggered to produce large amounts of effector molecules that dysregulate the immune system, which could manifest itself as autoimmunity or as a FasL-mediated neutropenia.
authors.affiliation: Division of Immunology and Allergology, University Hospital, Geneva, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Bigouret
authors.forename: Till
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Lionel
authors.initials: L
authors.lastname: Arlettaz
authors.forename: Jean
authors.initials: J
authors.lastname: Villard
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: André
authors.initials: A
authors.lastname: Ticheli
authors.forename: Alois
authors.initials: A
authors.lastname: Gratwohl
authors.forename: Kaveh
authors.initials: K
authors.lastname: Samii
authors.forename: Bernard
authors.initials: B
authors.lastname: Chapuis
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Eddy
authors.initials: E
authors.lastname: Roosnek
mesh_terms: D015703:Antigens, CD / Q000032:analysis*; D018959:CD57 Antigens / Q000032:analysis; D002454:Cell Differentiation; D002999:Clone Cells / Q000737:chemistry / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D037181:Lectins, C-Type / Q000032:analysis*; D015458:Leukemia, T-Cell / Q000276:immunology* / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins / Q000032:analysis*; D011971:Receptors, Immunologic / Q000032:analysis*; D055607:Receptors, Natural Killer Cell; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000276:immunology*; D016615:Telomere / Q000648:ultrastructure
chemical_list: D015703:Antigens, CD; D018959:CD57 Antigens; C527054:KLRC1 protein, human; C527059:KLRC2 protein, human; C497869:KLRD1 protein, human; C527085:KLRK1 protein, human; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D017493:Leukocyte Common Antigens