N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Kashirskoe sh., 24, 115478 Moscow, Russia.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya st. 16/10, 117997 Moscow, Russia.
Int J Mol Sci. 2023 Mar 30;24(7):6527. doi: 10.3390/ijms24076527.
A T cell receptor (TCR) consists of α- and β-chains. Accumulating evidence suggests that some TCRs possess chain centricity, i.e., either of the hemi-chains can dominate in antigen recognition and dictate the TCR's specificity. The introduction of TCRα/β into naive lymphocytes generates antigen-specific T cells that are ready to perform their functions. Transgenesis of the dominant active TCRα creates transgenic animals with improved anti-tumor immune control, and adoptive immunotherapy with TCRα-transduced T cells provides resistance to infections. However, the potential detrimental effects of the dominant hemi-chain TCR's expression in transgenic animals have not been well investigated. Here, we analyzed, in detail, the functional status of the immune system of recently generated 1D1a transgenic mice expressing the dominant active TCRα specific to the H2-K molecule. In their age dynamics, neither autoimmunity due to the random pairing of transgenic TCRα with endogenous TCRβ variants nor significant disturbances in systemic homeostasis were detected in these mice. Although the specific immune response was considerably enhanced in 1D1a mice, responses to third-party alloantigens were not compromised, indicating that the expression of dominant active TCRα did not limit immune reactivity in transgenic mice. Our data suggest that TCRα transgene expression could delay thymic involution and maintain TCRβ repertoire diversity in old transgenic mice. The detected changes in the systemic homeostasis in 1D1a transgenic mice, which are minor and primarily transient, may indicate variations in the ontogeny of wild-type and transgenic mouse lines.
T 细胞受体 (TCR) 由 α 和 β 链组成。越来越多的证据表明，一些 TCR 具有链中心性，即半链中的任一个都可以在抗原识别中占主导地位，并决定 TCR 的特异性。将 TCRα/β 引入未成熟的淋巴细胞中会产生针对抗原的特异性 T 细胞，这些细胞已经准备好发挥其功能。优势活性 TCRα 的转基因会产生具有改善的抗肿瘤免疫控制的转基因动物，并且用转导了 TCRα 的 T 细胞进行过继免疫疗法会提供对感染的抵抗力。然而，在转基因动物中表达优势半链 TCR 的潜在有害影响尚未得到很好的研究。在这里，我们详细分析了最近生成的 1D1a 转基因小鼠的免疫系统的功能状态，这些小鼠表达针对 H2-K 分子的优势活性 TCRα。在其年龄动态中，这些小鼠既没有由于转基因 TCRα 与内源性 TCRβ 变体的随机配对而导致的自身免疫，也没有检测到全身内稳态的显著紊乱。尽管 1D1a 小鼠的特异性免疫反应显著增强，但对第三方同种异体抗原的反应不受影响，这表明优势活性 TCRα 的表达并没有限制转基因小鼠的免疫反应性。我们的数据表明，TCRα 转基因表达可能会延迟胸腺萎缩，并维持老年转基因小鼠中 TCRβ 库的多样性。在 1D1a 转基因小鼠中检测到的全身内稳态变化较小且主要是短暂的，这可能表明野生型和转基因小鼠系的个体发生存在差异。
