Dawicki Wojciech, Bertram Edward M, Sharpe Arlene H, Watts Tania H
Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
J Immunol. 2004 Nov 15;173(10):5944-51. doi: 10.4049/jimmunol.173.10.5944.
Mice deficient in OX40 or 4-1BB costimulatory pathways show defects in T cell recall responses, with predominant effects on CD4 vs CD8 T cells, respectively. However, OX40L can also stimulate CD8 T cells and 4-1BBL can influence CD4 T cells, raising the possibility of redundancy between the two TNFR family costimulators. To test this possibility, we generated mice deficient in both 4-1BBL and OX40L. In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression. Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40. Thus, in vivo expression of 4-1BB and OX40 can be temporally and spatially segregated. In the absence of OX40L, there were decreased CD4 T cells late in the primary response and no detectable secondary expansion of adoptively transferred CD4 T cells under conditions in which primary expansion was unaffected. The 4-1BBL had a minor effect on the primary response of CD4 T cells in this model, but showed larger effects on the secondary response, although 4-1BBL(-/-) mice show less impairment in CD4 secondary responses than OX40L(-/-) mice. The 4-1BBL(-/-) and double knockout mice were similarly impaired in the CD8 T cell response, whereas OX40L(-/-) and double knockout mice were similarly impaired in the CD4 T cell response to both protein Ag and influenza virus. Thus, 4-1BB and OX40 act independently and nonredundantly to facilitate robust CD4 and CD8 recall responses.
OX40或4-1BB共刺激通路缺陷的小鼠在T细胞回忆反应中表现出缺陷，分别对CD4和CD8 T细胞有主要影响。然而，OX40L也可以刺激CD8 T细胞，4-1BBL可以影响CD4 T细胞，这增加了两种肿瘤坏死因子受体（TNFR）家族共刺激分子之间存在冗余的可能性。为了验证这种可能性，我们构建了同时缺乏4-1BBL和OX40L的小鼠。在过继转移模型中，CD4 T细胞在免疫反应中依次表达4-1BB和OX40，其表达时间几乎没有重叠或完全没有重叠。在相同条件下，CD8 T细胞表达4-1BB，但未检测到OX40。因此，4-1BB和OX40的体内表达在时间和空间上可以分离。在缺乏OX40L的情况下，初次反应后期CD4 T细胞数量减少，并且在初次扩增不受影响的条件下，过继转移的CD4 T细胞没有可检测到的二次扩增。在该模型中，4-1BBL对CD4 T细胞的初次反应影响较小，但对二次反应影响较大，尽管4-1BBL基因敲除（-/-）小鼠比OX40L基因敲除（-/-）小鼠的CD4二次反应受损程度更小。4-1BBL基因敲除（-/-）小鼠和双敲除小鼠在CD8 T细胞反应中同样受损，而OX40L基因敲除（-/-）小鼠和双敲除小鼠在对蛋白质抗原和流感病毒的CD4 T细胞反应中同样受损。因此，4-1BB和OX40独立且非冗余地发挥作用，以促进强大的CD4和CD8回忆反应。
