title: Pathologic clonal cytotoxic T-cell responses: nonrandom nature of the T-cell-receptor restriction in large granular lymphocyte leukemia.
abstract: T-cell large granular lymphocyte (T-LGL) leukemia is a clonal lymphoproliferation of cytotoxic T cells (CTLs) associated with cytopenias. T-LGL proliferation seems to be triggered/sustained by antigenic drive; it is likely that hematopoietic progenitors are the targets in this process. The antigen-specific portion of the T-cell receptor (TCR), the variable beta (VB)-chain complementarity-determining region 3 (CDR3), can serve as a molecular signature (clonotype) of a T-cell clone. We hypothesized that clonal CTL proliferation develops not randomly but in the context of an autoimmune response. We identified the clonotypic sequence of T-LGL clones in 60 patients, including 56 with known T-LGL and 4 with unspecified neutropenia. Our method also allowed for the measurement of clonal frequencies; a decrease in or loss of the pathogenic clonotype and restoration of the TCR repertoire was found after hematologic remission. We identified 2 patients with identical immunodominant CDR3 sequence. Moreover, we found similarity between multiple immunodominant clonotypes and codominant as well as a nonexpanded, "supporting" clonotypes. The data suggest a nonrandom clonal selection in T-LGL, possibly driven by a common antigen. In contrast, the physiologic clonal CTL repertoire is highly diverse and we were not able to detect any significant clonal sharing in 26 healthy controls.
authors.affiliation: Taussig Cancer Center/R40, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.forename: Christine
authors.initials: C
authors.lastname: O'Keefe
authors.forename: Evan C
authors.initials: EC
authors.lastname: Howe
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Risitano
authors.forename: Alexander
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Ilka
authors.initials: I
authors.lastname: Warshawsky
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002999:Clone Cells / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D007945:Leukemia, Lymphoid / Q000276:immunology* / Q000473:pathology*; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology*
chemical_list: D011948:Receptors, Antigen, T-Cell