Cannons J L, Lau P, Ghumman B, DeBenedette M A, Yagita H, Okumura K, Watts T H
Department of Immunology, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
J Immunol. 2001 Aug 1;167(3):1313-24. doi: 10.4049/jimmunol.167.3.1313.
A costimulatory member of the TNFR family, 4-1BB, is expressed on activated T cells. Although some reports have suggested that 4-1BB is primarily involved in CD8 T cell activation, in this report we demonstrate that both CD4 and CD8 T cells respond to 4-1BB ligand (4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells up-regulate 4-1BB, OX40, and CD27 and respond to 4-1BBL-mediated costimulation during a primary response to peptide Ag. 4-1BBL enhanced proliferation, cytokine production, and CTL effector function of TCR transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL under similar conditions of antigenic stimulation, we performed MLRs with purified CD4 or CD8 responders from CD28(+/+) and CD28(-/-) mice. We found that CD8 T cells produced IL-2 and IFN-gamma in a 4-1BBL-dependent manner, whereas under the same conditions the CD4 T cells produced IL-2 and IL-4. 4-1BBL promoted survival of CD4 and CD8 T cells, particularly at late stages of the MLR. CD4 and CD8 T cells both responded to anti-CD3 plus s4-1BBL with a similar cytokine profile as observed in the MLR. CD4 and CD8 T cells exhibited enhanced proliferation and earlier cell division when stimulated with anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL, and both subsets responded comparably to anti-CD3 plus 4-1BBL. These data support the idea that CD28 plays a primary role in initial T cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances cell division and T cell effector function.
肿瘤坏死因子受体（TNFR）家族的共刺激成员4-1BB在活化的T细胞上表达。尽管一些报告表明4-1BB主要参与CD8 T细胞活化，但在本报告中我们证明CD4和CD8 T细胞对4-1BB配体（4-1BBL）的反应具有相似的效力。CD4和CD8 TCR转基因T细胞上调4-1BB、OX40和CD27，并在对肽抗原的初次反应中对4-1BBL介导的共刺激作出反应。4-1BBL增强了TCR转基因T细胞的增殖、细胞因子产生和CTL效应功能。为了在相似的抗原刺激条件下比较CD4和CD8对4-1BBL的反应，我们用来自CD28(+/+)和CD28(-/-)小鼠的纯化CD4或CD8应答细胞进行了混合淋巴细胞反应（MLR）。我们发现CD8 T细胞以4-1BBL依赖的方式产生IL-2和IFN-γ，而在相同条件下CD4 T细胞产生IL-2和IL-4。4-1BBL促进了CD4和CD8 T细胞的存活，尤其是在MLR的后期。CD4和CD8 T细胞对抗CD3加s4-1BBL的反应与在MLR中观察到的细胞因子谱相似。与抗CD3加4-1BBL相比，用抗CD组3加抗CD28刺激时，CD4和CD8 T细胞表现出增强的增殖和更早的细胞分裂，并且两个亚群对抗CD3加4-1BBL的反应相当。这些数据支持这样的观点，即CD28在初始T细胞扩增中起主要作用，而4-1BB/4-1BBL维持CD4和CD8 T细胞反应，以及增强细胞分裂和T细胞效应功能。
