Pathologic clonal cytotoxic T-cell responses: nonrandom nature of the T-cell-receptor restriction in large granular lymphocyte leukemia.
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.
Wlodarski
Marcin W
MW
Taussig Cancer Center/R40, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
O'Keefe
Christine
C
Howe
Evan C
EC
Risitano
Antonio M
AM
Rodriguez
Alexander
A
Warshawsky
Ilka
I
Loughran
Thomas P
TP
Maciejewski
Jaroslaw P
JP
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*
D011948:Receptors, Antigen, T-Cell