Mukherjee Sambuddho, Ahmed Asma, Malu Shruti, Nandi Dipankar
Department of Biochemistry, Indian Institute of Science, Bangalore, India 560012.
J Leukoc Biol. 2006 Jul;80(1):66-74. doi: 10.1189/jlb.0505260. Epub 2006 Apr 19.
Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a well-studied T cell costimulatory receptor that is known to inhibit T cell activation. In this study, the relationship between strength of the first signal and costimulatory interactions on primary mouse CD4(+) T cells was investigated. CTLA4-CD80/CD86 interactions differentially modulate T cell cycling based on the mode of CD3 signal: Activation with plate-bound (pb) anti-CD3 generates a strong signal compared with a weak signal with soluble (sol) anti-CD3, resulting in approximately sevenfold higher amounts of interleukin (IL)-2 and an increase in cell cycling. Activation of T cells with sol anti-CD3 (weak signal) together with CTLA4-CD80/CD86 blockade lowers IL-2 production and cell cycling, demonstrating an enhancing role for these interactions. Conversely, blockade of CTLA4-CD80/CD86 interactions on T cells activated with pb anti-CD3 (strong signal) increases proliferation, which is consistent with CTLA4 as a negative regulator. Also, coculture of T cells with Chinese hamster ovary cells expressing CD80 or CD86 demonstrates that the strength of the primary signal plays an important role. It is important that modulation of IL-2 amounts leads to distinct alterations in the functional effects of CTLA4-CD80/CD86 interactions. On increasing IL-2 amounts, activation of T cells stimulated with sol anti-CD3 (weak signal) and CTLA4-CD80/CD86 blockade is greater compared with control. Concurrently, neutralization of IL-2 greatly reduces activation of T cells stimulated with pb anti-CD3 (strong signal) and CTLA4-CD80/CD86 blockade compared with control. These results underscore the importance of strength of first signal, CTLA4-CD80/CD86 interactions, and IL-2 amounts in modulating primary CD4(+) T cell responses.
细胞毒性T淋巴细胞抗原4（CTLA4）是一种经过充分研究的T细胞共刺激受体，已知其可抑制T细胞活化。在本研究中，对原代小鼠CD4(+) T细胞上第一信号强度与共刺激相互作用之间的关系进行了研究。基于CD3信号模式，CTLA4-CD80/CD86相互作用对T细胞周期的调节存在差异：与可溶性（sol）抗CD3产生的弱信号相比，用板结合（pb）抗CD3激活产生强信号，导致白细胞介素（IL）-2的量增加约7倍，并使细胞周期增加。用sol抗CD3（弱信号）激活T细胞并同时阻断CTLA4-CD80/CD86会降低IL-2产生和细胞周期，表明这些相互作用具有增强作用。相反，在由pb抗CD3（强信号）激活的T细胞上阻断CTLA4-CD80/CD86相互作用会增加增殖，这与CTLA4作为负调节因子一致。此外，T细胞与表达CD80或CD86的中国仓鼠卵巢细胞共培养表明，第一信号的强度起着重要作用。重要的是，IL-2量的调节会导致CTLA4-CD80/CD86相互作用的功能效应发生明显改变。随着IL-2量的增加，与对照相比，用sol抗CD3（弱信号）刺激并阻断CTLA4-CD80/CD86的T细胞激活程度更高。同时，与对照相比，中和IL-2会大大降低用pb抗CD3（强信号）刺激并阻断CTLA4-CD80/CD86的T细胞的激活。这些结果强调了第一信号强度、CTLA4-CD80/CD86相互作用和IL-2量在调节原代CD4(+) T细胞反应中的重要性。
