Ohnuki Kazunobu, Watanabe Yuri, Takahashi Yusuke, Kobayashi Sakiko, Watanabe Shiho, Ogawa Shuhei, Kotani Motoko, Kozono Haruo, Tanabe Kazunari, Abe Ryo
Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
Biochem Biophys Res Commun. 2009 Mar 20;380(4):742-7. doi: 10.1016/j.bbrc.2009.01.123. Epub 2009 Jan 25.
In order to fully understand T cell-mediated immunity, the mechanisms that regulate clonal expansion and cytokine production by CD4(+) antigen-specific effector T cells in response to a wide range of antigenic stimulation needs clarification. For this purpose, panels of antigen-specific CD4(+) T cell clones with different thresholds for antigen-induced proliferation were generated by repeated stimulation with high- or low-dose antigen. Differences in antigen sensitivities did not correlate with expression of TCR, CD4, adhesion or costimulatory molecules. There was no significant difference in antigen-dependent cytokine production by TG40 cells transfected with TCR obtained from either high- or low-dose-responding T cell clones, suggesting that the affinity of TCRs for their ligands is not primary determinant of T cell antigen reactivity. The proliferative responses of all T cell clones to both peptide stimulation and to TCRbeta crosslinking revealed parallel dose-response curves. These results suggest that the TCR signal strength of effector T cells and threshold of antigen reactivity is determined by an intrinsic property, such as the TCR signalosome and/or intracellular signaling machinery. Finally, the antigen responses of high- and low-peptide-responding T cell clones reveal that clonal expansion and cytokine production of effector T cells occur independently of antigen concentration. Based on these results, the mechanisms underlying selection of high "avidity" effector and memory T cells in response to pathogen are discussed.
为了全面理解T细胞介导的免疫，需要阐明调节CD4(+)抗原特异性效应T细胞在广泛抗原刺激下克隆扩增和细胞因子产生的机制。为此，通过用高剂量或低剂量抗原反复刺激，产生了具有不同抗原诱导增殖阈值的抗原特异性CD4(+) T细胞克隆组。抗原敏感性的差异与TCR、CD4、黏附分子或共刺激分子的表达无关。用从高剂量或低剂量反应性T细胞克隆获得的TCR转染的TG40细胞在抗原依赖性细胞因子产生方面没有显著差异，这表明TCR与其配体的亲和力不是T细胞抗原反应性的主要决定因素。所有T细胞克隆对肽刺激和TCRβ交联的增殖反应均显示出平行的剂量反应曲线。这些结果表明，效应T细胞的TCR信号强度和抗原反应阈值由内在特性决定，如TCR信号体和/或细胞内信号传导机制。最后，高肽和低肽反应性T细胞克隆的抗原反应表明，效应T细胞的克隆扩增和细胞因子产生与抗原浓度无关。基于这些结果，讨论了在对病原体的反应中选择高“亲和力”效应T细胞和记忆T细胞的潜在机制。
