Gerwien J, Kaltoft K, Nielsen M, Nielsen M B, Svejgaard A, Geisler C, Röpke C, Odum N
Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
Tissue Antigens. 1998 Feb;51(2):164-73. doi: 10.1111/j.1399-0039.1998.tb02961.x.
T cells expressing the appropriate T-cell receptor Vbeta chain proliferate in response to Staphylococcus enterotoxin A (SEA) pulsed antigen-presenting cells (APC), whereas other T cells do not (SEA "non-responders"). Activated human T cells express MHC class II molecules that are high affinity receptors for SEA. Here we show that, in the absence of APC, SEA induces a profound inhibition of IL-15-driven proliferation in MHC class II+, human SEA-"responder" T-cell lines. In contrast, proliferation induced by phorbol esther (PMA) was enhanced by SEA. The inhibitory effect on cytokine-mediated mitogenesis correlates with an inhibition of IL-2Rbeta expression and ligand-induced tyrosine phosphorylation of IL-2R. Cyclosporin A (CyA), an inhibitor of the protein phosphatase (PP2B) calcineurin, strongly inhibits the SEA-induced modulations of cytokine receptor expression. Moreover, CyA inhibits both the anti-mitogenic effect of SEA on cytokine-induced proliferation and the pro-mitogenic effect of PMA. In contrast, inhibitors of PP1, PP2A, protein kinase C (PKC), phosphatidyl-inositol-3-kinase (PI-3K) and mammalian target of rapamycin (mTOR) are unable to inhibit the effects of SEA. In a SEA "non-responder" T-cell clone obtained from the affected skin of a patient with psoriasis vulgaris, SEA does not inhibit IL-2Rbeta expression and IL-15-driven proliferation. On the contrary, SEA enhances IL-15- and IL-2-induced proliferation via a CyA-sensitive pathway in this T-cell clone. In conclusion, the present data show that (i) SEA selectively inhibits IL-15- (but not PMA-) mediated proliferation in SEA "responder" T cells, (ii) SEA enhances cytokine-driven growth in psoriasis T cells with a "non-responder" phenotype, and (iii) crosstalk between SEA receptors and the IL-15R (and IL-2R) pathway is mediated via a PP2B-dependent and PP1/PP2A-, PKC-, PI-3 kinase- and mTOR-independent pathway in human T-cell lines.
表达适当T细胞受体Vβ链的T细胞会对用葡萄球菌肠毒素A（SEA）脉冲处理的抗原呈递细胞（APC）做出增殖反应，而其他T细胞则不会（SEA“无反应者”）。活化的人T细胞表达对SEA具有高亲和力的MHC II类分子。在此我们表明，在没有APC的情况下，SEA会在MHC II +、人SEA“反应者”T细胞系中对IL-15驱动的增殖产生显著抑制作用。相反，佛波酯（PMA）诱导的增殖会被SEA增强。对细胞因子介导的有丝分裂的抑制作用与IL-2Rβ表达的抑制以及IL-2R的配体诱导的酪氨酸磷酸化相关。环孢素A（CyA），一种蛋白磷酸酶（PP2B）钙调神经磷酸酶的抑制剂，强烈抑制SEA诱导的细胞因子受体表达的调节。此外，CyA既抑制SEA对细胞因子诱导的增殖的抗有丝分裂作用，也抑制PMA的促有丝分裂作用。相反，PP1、PP2A、蛋白激酶C（PKC）、磷脂酰肌醇-3激酶（PI-3K）和雷帕霉素哺乳动物靶标（mTOR）的抑制剂无法抑制SEA的作用。在从一名寻常型银屑病患者受影响皮肤中获得的SEA“无反应者”T细胞克隆中，SEA不会抑制IL-2Rβ表达和IL-15驱动的增殖。相反，在该T细胞克隆中，SEA通过一条对CyA敏感的途径增强IL-15和IL-2诱导的增殖。总之，目前的数据表明：（i）SEA选择性抑制SEA“反应者”T细胞中IL-15介导的增殖（但不抑制PMA介导的增殖）；（ii）SEA增强具有“无反应者”表型的银屑病T细胞中细胞因子驱动的生长；（iii）在人T细胞系中，SEA受体与IL-15R（和IL-2R）途径之间的相互作用是通过一条PP2B依赖性且不依赖PP1/PP2A、PKC、PI-3激酶和mTOR的途径介导的。
