Martínez-Barnetche Jesús, Madrid-Marina Vicente, Flavell Richard A, Moreno José
Research Unit on Autoimmune Diseases, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 03020 México City, Distrito Federal, México.
J Immunol. 2002 Feb 1;168(3):1042-9. doi: 10.4049/jimmunol.168.3.1042.
Binding of CD154 to its receptor, CD40, provides costimulation for mature B cell activation and differentiation in response to Ag receptor signals. In mice, early B cell precursors express CD40, but its function at this stage is unknown. We examined the effects of CD40 ligation during B cell ontogeny in transgenic mice constitutively expressing CD154 on B cells (kappaEP-CD154). Precursors beyond pro-B cells were absent in adult bone marrow but were increased in the fetal liver. Newborn kappaEP-CD154 mice had largely increased numbers of peripheral B cells, which were CD154+, and that 36 h after birth expressed high surface levels of CD23 and MHC class II, resembling activated mature B cells. Nevertheless, kappaEP-CD154 mice were hypogammaglobulinemic, indicating that the expanded population of apparently activated B cells was nonfunctional. Further analysis revealed that soon after birth, kappaEP-CD154 mice-derived B cells became CD5+/Fas+, after which progressively decreased in the periphery in a CD154-CD40-dependent manner. These results indicate that CD40 ligation during B cell ontogeny induces negative selection characterized by either hyporesponsiveness or an arrest in maturation depending on the time of analysis and the anatomic site studied.
CD154与其受体CD40的结合为成熟B细胞在响应抗原受体信号时的激活和分化提供共刺激。在小鼠中，早期B细胞前体表达CD40，但其在此阶段的功能尚不清楚。我们在组成性表达B细胞上的CD154的转基因小鼠（kappaEP-CD154）中研究了B细胞个体发育过程中CD40连接的影响。成年骨髓中除前B细胞外的前体细胞缺失，但在胎肝中增加。新生的kappaEP-CD154小鼠外周B细胞数量大幅增加，这些B细胞是CD154阳性，并且在出生后36小时表达高水平的CD23和II类主要组织相容性复合体，类似于活化的成熟B细胞。然而，kappaEP-CD154小鼠是低丙种球蛋白血症，表明明显活化的B细胞扩增群体无功能。进一步分析显示，出生后不久，kappaEP-CD154小鼠来源的B细胞变成CD5阳性/Fas阳性，之后以CD154-CD40依赖的方式在外周逐渐减少。这些结果表明，B细胞个体发育过程中的CD40连接诱导阴性选择，其特征取决于分析时间和所研究的解剖部位，表现为低反应性或成熟停滞。
