Lee Seung-Joo, Myers Lara, Muralimohan Guruprasaadh, Dai Jie, Qiao Yi, Li Zihai, Mittler Robert S, Vella Anthony T
Division of Immunology, University of Connecticut Health Center, Farmington 06032, USA.
J Immunol. 2004 Sep 1;173(5):3002-12. doi: 10.4049/jimmunol.173.5.3002.
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, effector 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 4-1BB and OX40 induces a massive burst of CD8 T cell effector function sufficient to therapeutically treat established tumors even under immunocompromising conditions.
CD40、4-1BB和OX40是属于肿瘤坏死因子/神经生长因子超家族受体的共刺激分子。我们使用几种不同的小鼠体内追踪模型，研究了同时共刺激是否会影响T细胞的反应。我们发现，通过4-1BB和OX40而非CD40进行的强制双重共刺激，可诱导特异性CD8 T细胞的深度克隆扩增。相比之下，特异性CD4 T细胞对双重共刺激的反应是相加性的而非协同性的。特异性CD8 T细胞的协同反应持续数周，扩增的效应细胞存在于整个淋巴组织和非淋巴组织中。与单一共刺激剂相比，通过4-1BB和OX40进行的双重共刺激既没有增加BrdU掺入，也没有增加T细胞分裂的轮数，而是以细胞内在方式增强了积累。从机制上讲，我们发现CD8 T细胞的克隆扩增和效应功能并不需要T细胞辅助，但在（非）淋巴组织中的积累主要依赖于CD4 T细胞。为了确定这种方法在生理环境中是否有用，我们证明了双重共刺激介导了对已建立的小鼠肉瘤的排斥反应。重要的是，针对已建立肿瘤的效应功能依赖于CD8 T细胞，而完全不依赖于CD4 T细胞，并且强制双重共刺激的时机受到精确调控。总的来说，这些数据表明，通过4-1BB和OX40同时进行双重共刺激可诱导大量CD8 T细胞效应功能的爆发，即使在免疫受损条件下也足以对已建立的肿瘤进行治疗。
