Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells

被引:385
作者
Grossman, WJ
Verbsky, JW
Tollefsen, BL
Kemper, C
Atkinson, JP
Ley, TJ
机构
[1] Washington Univ, Sch Med, Siteman Canc Ctr, Dept Internal Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Div Rheumatol, St Louis, MO 63110 USA
[3] St Louis Childrens Hosp, Div Rheumatol, St Louis, MO 63178 USA
[4] St Louis Childrens Hosp, Dept Pediat, Div Hematol Oncol, St Louis, MO 63178 USA
关键词
D O I
10.1182/blood-2004-03-0859
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the perforin/granzyme pathway as a major mechanism to kill pathogen-containing cells and tumor cells.' 2 Dysregulation of this pathway results in several human diseases, such as hemophagocytic lymphohistiocytosis. Here we characterize the single-cell expression pattern of granzymes A and B in human lymphocytes using a flow cytometry-based assay. We demonstrate that most circulating CD56(+)8(-) NK cells, and approximately half of circulating CD8(+) T lymphocytes, coexpressed both granzymes A and B. In contrast, few circulating CD4(+) T lymphocytes expressed granzymes A or B. Activation of CD8(+) T lymphocytes with concanavalin A (ConA)/interleukin-2 (IL-2), and activation of CD4(+) T lymphocytes with antibodies to CD3/CD28 or CD3/CD46 (to generate T regulatory [Tr1] cells), induced substantial expression of granzyme B, but not granzyme A. Naive CD4(+)CD45RA(+) cells stimulated with antibodies to CD3/CD46 strongly expressed granzyme B, while CD3/CD28 stimulation was ineffective. Finally, we show that granzyme B-expressing CD4(+) TO cells are capable of killing target cells in a perforin-dependent, but major histocompatibility complex (MHC)/T-cell receptor (TCR)-independent, manner. Our results demonstrate discordant expression of granzymes A and B in human lymphocyte subsets and T regulatory cells, which suggests that different granzymes may play unique roles in immune system responses and regulation. (C) 2004 by The American Society of Hematology.
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页码:2840 / 2848
页数:9
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