4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function

被引:96
作者
Lee, SJ
Myers, L
Muralimohan, G
Dai, J
Qiao, Y
Li, ZH
Mittler, RS
Vella, AT
机构
[1] Univ Connecticut, Ctr Hlth, Div Immunol, Farmington, CT 06032 USA
[2] Univ Connecticut, Ctr Hlth, Ctr Immunotherapy Canc & Infect Dis, Farmington, CT 06032 USA
[3] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30329 USA
[4] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30329 USA
关键词
D O I
10.4049/jimmunol.173.5.3002
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
CD40, 4-1BB, and OX40 are costimulatory molecules belonging to the TNF/nerve growth factor superfamily of receptors. We examined whether simultaneous costimulation affected the responses of T cells using several different in vivo tracking models in mice. We show that enforced dual costimulation through 4-1BB and OX40, but not through CD40, induced profound specific CD8 T cell clonal expansion. In contrast, the response of specific CD4 T cells to dual costimulation was additive rather than synergistic. The synergistic response of the specific CD8 T cells persevered for several weeks, and the expanded effector cells resided throughout lymphoid and nonlymphoid tissue. Dual costimulation through 4-1BB and OX40 did not increase BrdU incorporation nor an increase in the number of rounds of T cell division in comparison to single costimulators, but rather enhanced accumulation in a cell-intrinsic manner. Mechanistically speaking, we show that CD8 T cell clonal expansion and effector function did not require T help, but accumulation in (non)lymphoid tissue was predominantly CD4 T cell dependent. To determine whether this approach would be useful in a physiological setting, we demonstrated that dual costimulation mediated rejection of an established murine sarcoma. Importantly, elector function directed toward established tumors was CD8 T cell dependent while being entirely CD4 T cell independent, and the timing of enforced dual costimulation was exquisitely regulated. Collectively, these data suggest that simultaneous dual costimulation through 4-IBB and OX40 induces a massive burst of CD8 T cell effector function sufficient to therapeutically treat established tumors even under immunocompromising conditions.
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收藏
页码:3002 / 3012
页数:11
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