The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, P.O. Box 1125 Blindern, N-0317 Oslo, Norway.
Cell Signal. 2011 Jun;23(6):1009-16. doi: 10.1016/j.cellsig.2010.11.018. Epub 2010 Dec 2.
The canonical second messenger cAMP is well established as a potent negative regulator of T cell immune function. Through protein kinase A (PKA) it regulates T cell function at the level of transcription factors, members of the mitogen-activated protein kinase pathway, phospholipases (PLs), Ras homolog (Rho)A and proteins involved in the control of cell cycle progression. Type I PKA is the predominant PKA isoform in T cells. Furthermore, whereas type II PKA is located at the centrosome, type I PKA is anchored close to the T cell receptor (TCR) in lipid rafts by the Ezrin-ERM-binding phosphoprotein of 50 kDa (EBP50)-phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG) scaffold complex. The most TCR-proximal target for type I PKA is C-terminal Src kinase (Csk), which upon activation by raft recruitment and phosphorylation inhibits the Src family tyrosine kinases Lck and Fyn and thus functions to maintain T cell homeostasis. Recently, induction of cAMP levels in responder T cells has emerged as one of the mechanisms by which regulatory T (T(R)) cells execute their suppressive action. Thus, the cAMP-type I PKA-Csk pathway emerges as a putative target for therapeutic intervention in autoimmune disorders as well as in cancer, where T(R) cell-mediated suppression contributes to suboptimal local immune responses.
经典的第二信使 cAMP 已被充分证实为 T 细胞免疫功能的有效负调控因子。通过蛋白激酶 A（PKA），它在转录因子、丝裂原活化蛋白激酶途径成员、磷脂酶（PL）、Ras 同源（Rho）A 和参与细胞周期进程控制的蛋白水平上调节 T 细胞功能。I 型 PKA 是 T 细胞中主要的 PKA 同工型。此外，虽然 II 型 PKA 位于中心体，但 I 型 PKA 通过 50 kDa 的 Ezrin-ERM 结合磷蛋白（EBP50）与富含糖脂的微区（PAG）支架复合物锚定在靠近 T 细胞受体（TCR）的脂质筏上。I 型 PKA 最接近 TCR 的靶标是 C 端Src 激酶（Csk），它通过筏募集和磷酸化激活，抑制Src 家族酪氨酸激酶 Lck 和 Fyn，从而维持 T 细胞的内稳态。最近，在应答性 T 细胞中诱导 cAMP 水平已成为调节性 T（T(R)）细胞发挥其抑制作用的机制之一。因此，cAMP-I 型 PKA-Csk 途径成为自身免疫性疾病以及癌症中治疗干预的潜在靶点，在这些疾病中，T(R)细胞介导的抑制作用导致局部免疫反应不理想。
