Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

被引:35
作者
Lee-Chang, Catalina [1 ]
Bodogai, Monica [1 ]
Moritoh, Kanako [1 ]
Olkhanud, Purevdorj B. [1 ]
Chan, Andrew C. [2 ]
Croft, Michael [3 ]
Mattison, Julie A. [4 ]
Holst, Peter Johannes [5 ]
Gress, Ronald E. [6 ]
Ferrucci, Luigi [7 ]
Hakim, Fran [6 ]
Biragyn, Arya [1 ]
机构
[1] Lab Mol Biol & Immunol, Immunoregulat Sect, Baltimore, MD USA
[2] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA
[3] La Jolla Inst Allergy & Immunol, Div Immune Regulat, La Jolla, CA USA
[4] NIA, Nonhuman Primate Core Facil, Translat Gerontol Branch, Baltimore, MD 21224 USA
[5] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Lab Expt Vaccinol, DK-1168 Copenhagen, Denmark
[6] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA
[7] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Baltimore, MD 21224 USA
关键词
ANTIGEN-PRESENTING CELLS; HEMATOPOIETIC STEM-CELLS; IN-VIVO; RHEUMATOID-ARTHRITIS; OLD MICE; CANCER; IMMUNE; SURVIVAL; EXPANSION; AGE;
D O I
10.1182/blood-2014-03-563940
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+) CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques, and mice, and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+) CD8(+) T cells by presenting endogenous antigens and using the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and its capacity to evoke the generation of GrB(+) CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly.
引用
收藏
页码:1450 / 1459
页数:10
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