Reif K, Lucas S, Cantrell D
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
Curr Biol. 1997 May 1;7(5):285-93. doi: 10.1016/s0960-9822(06)00151-5.
A delicate balance between positive and negative regulatory mechanisms during T-cell activation determines the specificity and magnitude of an immune response. Phosphoinositide 3-kinase (PI 3-kinase) is activated by a diverse set of receptors that determine T-cell function, including the T-cell antigen receptor (TCR), the costimulatory receptor CD28, and negative regulators of T-cell activation such as CTLA-4. PI 3-kinase is also regulated by the haematopoietic cytokines that determine T-cell differentiation and lymphocyte proliferation. PI 3-kinase can thus dynamically influence the outcome of the immune reactions at various stages. In this study, we investigated the importance of PI 3-kinase in TCR-directed T-cell activation using activated or inhibitory versions of PI 3-kinase.
Certain aspects of TCR responses such as the induction of transcriptional activity of AP1 and serum response factor were not affected by expression of the mutant forms of PI 3-kinase. We found, however, that PI 3-kinase profoundly influenced the transactivation capacity of 'nuclear factor of activated T cells' (NF-AT) elicited by the TCR: expression of an activated form of PI 3-kinase inhibited TCR-mediated NF-AT responses, whereas expression of a dominant negative mutant of PI 3-kinase potently enhanced TCR-controlled NF-AT induction. These effects of PI 3-kinase were not mediated by previously identified PI 3-kinase effectors, such as protein kinase B, a positive regulator of PI 3-kinase, or the GTPase Rac, and are therefore likely to involve a novel, as yet unknown, effector molecule.
Our results establish that PI 3-kinase can both positively and negatively regulate T-cell function, and uncover a previously unrecognized function for PI 3-kinase in T cells as a selective negative regulator of TCR-signalling events and therefore as a determinant of T-cell homeostasis.
T细胞活化过程中正负调节机制之间的微妙平衡决定了免疫反应的特异性和强度。磷酸肌醇3激酶（PI 3激酶）可被多种决定T细胞功能的受体激活，包括T细胞抗原受体（TCR）、共刺激受体CD28以及T细胞活化的负调节因子如CTLA-4。PI 3激酶也受决定T细胞分化和淋巴细胞增殖的造血细胞因子调控。因此，PI 3激酶可在不同阶段动态影响免疫反应的结果。在本研究中，我们使用PI 3激酶的激活型或抑制型来研究PI 3激酶在TCR介导的T细胞活化中的重要性。
TCR反应的某些方面，如AP1和血清反应因子转录活性的诱导，不受PI 3激酶突变形式表达的影响。然而，我们发现PI 3激酶深刻影响了TCR引发的“活化T细胞核因子”（NF-AT）的反式激活能力：PI 3激酶激活型的表达抑制了TCR介导的NF-AT反应，而PI 3激酶显性负突变体的表达则有力地增强了TCR控制的NF-AT诱导。PI 3激酶的这些作用不是由先前确定的PI 3激酶效应器介导的，如PI 激酶的正调节因子蛋白激酶B或GTP酶Rac，因此可能涉及一种新的、尚未知晓的效应分子。
我们的结果表明PI 3激酶可对T细胞功能进行正向和负向调节，并揭示了PI 3激酶在T细胞中一种先前未被认识的功能，即作为TCR信号事件的选择性负调节因子，因此也是T细胞稳态的决定因素。
