Institut Pasteur, Département d’Immunologie, Unité d’Allergologie Moléculaire & Cellulaire, Paris, France.
Immunol Lett. 2012 Mar 30;143(1):28-33. doi: 10.1016/j.imlet.2012.02.007.
When dimerized by Stem Cell Factor (SCF), the Receptor Tyrosine Kinase Kit triggers the proliferation of hematopoietic progenitors, including pro-B cells, and of some differentiated cells, including mast cells. We found previously that anti-Kit antibodies can mimic SCF and that anti-Kit-induced mast cell proliferation can be inhibited by the low-affinity IgG receptors FcγRIIB, when the two receptors are co-aggregated by IgG immune complexes. We show here that the same immune complexes inhibited anti-Kit-induced proliferation of Ba/F3 pro-B cells expressing wt Kit and FcγRIIB and that inhibition required the intracytoplasmic domain of FcγRIIB. Constitutively active Kit mutants are oncogenic. We show that Kit-dependent, ligand-independent proliferation of Ba/F3 cells expressing a constitutively dimerized Kit mutant was also inhibited by IgG immune complexes via FcγRIIB. FcγRIIB-dependent negative regulation therefore also affects Kit-dependent proliferation of transformed cells. Interestingly, the co-aggregation of Kit with FcγRIIB by immune complexes containing SCF also inhibited both growth factor-dependent and growth factor-independent proliferation of Ba/F3 cells expressing wt or mutated Kit, respectively. These results provide the basis for novel immunotherapeutical approaches of FcγRIIB-expressing tumors.
当干细胞因子 (SCF) 使受体酪氨酸激酶 Kit 二聚化时，它会触发造血祖细胞（包括前 B 细胞）和一些分化细胞（包括肥大细胞）的增殖。我们之前发现，抗 Kit 抗体可以模拟 SCF，并且当两个受体通过 IgG 免疫复合物共同聚集时，低亲和力 IgG 受体 FcγRIIB 可以抑制抗 Kit 诱导的肥大细胞增殖。我们在这里表明，相同的免疫复合物抑制了表达 wt Kit 和 FcγRIIB 的 Ba/F3 前 B 细胞的抗 Kit 诱导增殖，并且抑制需要 FcγRIIB 的细胞内结构域。组成性激活的 Kit 突变体是致癌的。我们表明，表达组成性二聚化 Kit 突变体的 Ba/F3 细胞的 Kit 依赖性、配体非依赖性增殖也通过 FcγRIIB 被 IgG 免疫复合物抑制。因此，FcγRIIB 依赖性负调节也会影响转化细胞的 Kit 依赖性增殖。有趣的是，含有 SCF 的免疫复合物中 Kit 与 FcγRIIB 的共同聚集也分别抑制了表达 wt 或突变 Kit 的 Ba/F3 细胞的生长因子依赖性和生长因子非依赖性增殖。这些结果为 FcγRIIB 表达肿瘤的新型免疫治疗方法提供了基础。
