T cell repertoire in patients with multiple myeloma and monoclonal gammopathy of undetermined significance: clonal CD8+ T cell expansions are found preferentially in patients with a low tumor burden.
The T cell receptor (TCR) variable (V) gene repertoire was analyzed in patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 17), multiple myeloma (MM) stage I (n = 16), MM stages II/III (n = 31) and age-matched controls (n = 27) by immunofluorescence and flow cytometry using a panel of mouse monoclonal antibodies (mAb) (n = 10) against TCR V alpha and V beta gene products. T cell expansion was defined as a value > or = thrice the normal median value for each respective TCR V mAb. Fifty-three percent of all patients displayed CD8+ expansion(s) as compared to 30% of age-matched controls (p < 0.001). Within the CD4 subset, 18% of the patients displayed T cell expansion(s) in comparison to 11% of the controls (not significant). Interestingly, the CD8+ expansion(s) were more frequently noted in patients with a low tumor burden (MGUS/MMI) (73%) as compared to those with advanced disease (MM II/III) (32% and control donors (30%) (p < 0.01). Likewise, multiple CD8+ expansions (two or more) were more common in MGUS/MM I patients than in MM II/III and controls (p < 0.01). The T cell expansions were stable over time in patients with a stable disease. A high degree of clonality of the expansions was detected by TCR CDR3 fragment length analysis, determination of J beta gene usage and nucleotide sequencing. The frequent finding of oligoclonal CD8+ T cell expansions in patients with a low tumor mass, but not in patients with advanced disease justifies further work in order to identify the relevance of expanded CD8+ T cells. In one patient with T cell reactivity against the autologous myeloma idiotype, two expansions within the CD8 population (V beta 3 and V beta 5.2 respectively) displayed no reactivity against the idiotype. Instead, idiotype recognition was confined to a CD8 non-expanded V beta 22+ T cell population, with a highly restricted TCR usage (CDR3 fragment length analysis).
Halapi
E
E
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.
Werner
A
A
Wahlström
J
J
Osterborg
A
A
Jeddi-Tehrani
M
M
Yi
Q
Q
Janson
C H
CH
Wigzell
H
H
Grunewald
J
J
Mellstedt
H
H
D000328:Adult; D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002999:Clone Cells; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019674:Genes, T-Cell Receptor beta / Q000235:genetics*; D006801:Humans; D018655:Lymphocyte Count; D051379:Mice; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000276:immunology* / Q000473:pathology; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*
D000951:Antigens, Neoplasm; D016693:Receptors, Antigen, T-Cell, alpha-beta