Institute for Biomedical Research of Cadiz (INIBICA), 11009 Cadiz, Spain.
Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz, 11002 Cadiz, Spain.
Int J Mol Sci. 2023 Feb 26;24(5):4574. doi: 10.3390/ijms24054574.
T lymphocytes are key players in adaptive immune responses through the recognition of peptide antigens through the T Cell Receptor (TCR). After TCR engagement, a signaling cascade is activated, leading to T cell activation, proliferation, and differentiation into effector cells. Delicate control of activation signals coupled to the TCR is needed to avoid uncontrolled immune responses involving T cells. It has been previously shown that mice deficient in the expression of the adaptor NTAL (Non-T cell activation linker), a molecule structurally and evolutionarily related to the transmembrane adaptor LAT (Linker for the Activation of T cells), develop an autoimmune syndrome characterized by the presence of autoantibodies and enlarged spleens. In the present work we intended to deepen investigation into the negative regulatory functions of the NTAL adaptor in T cells and its potential relationship with autoimmune disorders. For this purpose, in this work we used Jurkat cells as a T cell model, and we lentivirally transfected them to express the NTAL adaptor in order to analyze the effect on intracellular signals associated with the TCR. In addition, we analyzed the expression of NTAL in primary CD4+ T cells from healthy donors and Rheumatoid Arthritis (RA) patients. Our results showed that NTAL expression in Jurkat cells decreased calcium fluxes and PLC-γ1 activation upon stimulation through the TCR complex. Moreover, we showed that NTAL was also expressed in activated human CD4+ T cells, and that the increase of its expression was reduced in CD4+ T cells from RA patients. Our results, together with previous reports, suggest a relevant role for the NTAL adaptor as a negative regulator of early intracellular TCR signaling, with a potential implication in RA.
T 淋巴细胞通过 T 细胞受体 (TCR) 识别肽抗原，是适应性免疫反应的关键参与者。TCR 结合后，会激活信号级联反应，导致 T 细胞活化、增殖，并分化为效应细胞。需要精细控制与 TCR 相关的激活信号，以避免涉及 T 细胞的失控免疫反应。先前已经表明，表达衔接蛋白 NTAL（非 T 细胞激活接头）的小鼠会出现自身免疫综合征，其特征是存在自身抗体和脾脏肿大，而 NTAL 是一种与跨膜衔接子 LAT（T 细胞激活的衔接子）在结构和进化上相关的分子。在本工作中，我们旨在深入研究 NTAL 衔接子在 T 细胞中的负调控功能及其与自身免疫紊乱的潜在关系。为此，我们在这项工作中使用 Jurkat 细胞作为 T 细胞模型，并通过慢病毒转染使其表达 NTAL 衔接子，以分析其对与 TCR 相关的细胞内信号的影响。此外，我们还分析了来自健康供体和类风湿关节炎 (RA) 患者的原代 CD4+T 细胞中的 NTAL 表达。我们的结果表明，Jurkat 细胞中 NTAL 的表达降低了 TCR 复合物刺激后钙通量和 PLC-γ1 的激活。此外，我们还表明，NTAL 也在激活的人 CD4+T 细胞中表达，并且 RA 患者的 CD4+T 细胞中其表达的增加减少。我们的结果与之前的报告一起表明，NTAL 衔接子作为 TCR 信号转导早期的负调控因子具有重要作用，可能与 RA 有关。
