Renshaw B R, Fanslow W C, Armitage R J, Campbell K A, Liggitt D, Wright B, Davison B L, Maliszewski C R
Department of Molecular Immunology, Immunex Research and Development Corporation, Seattle, Washington 98101.
J Exp Med. 1994 Nov 1;180(5):1889-900. doi: 10.1084/jem.180.5.1889.
Individuals with X-linked hyper-IgM syndrome fail to express functional CD40 ligand (CD40L) and, as a consequence, are incapable of mounting protective antibody responses to opportunistic bacterial infections. To address the role of CD40L in humoral immunity, we created, through homologous recombination, mice deficient in CD40L expression. These mice exhibited no gross developmental deficiencies or health abnormalities and contained normal percentages of B and T cell subpopulations. CD40L-deficient mice did display selective deficiencies in humoral immunity; basal serum isotype levels were significantly lower than observed in normal mice, and IgE was undetectable. Furthermore, the CD40L-deficient mice failed to mount secondary antigen-specific responses to immunization with a thymus-dependent antigen, trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH). By contrast, the CD40L-deficient mice produced antigen-specific antibody of all isotypes except IgE in response to the thymus-independent antigen, DNP-Ficoll. These results underscore the requirement of CD40L for T cell-dependent antibody responses. Moreover, Ig class switching to isotypes other than IgE can occur in vivo in the absence of CD40L, supporting the notion that alternative B cell signaling pathways regulate responses to thymus-independent antigens.
患有X连锁高IgM综合征的个体无法表达功能性CD40配体（CD40L），因此，他们无法对机会性细菌感染产生保护性抗体反应。为了研究CD40L在体液免疫中的作用，我们通过同源重组创建了缺乏CD40L表达的小鼠。这些小鼠没有明显的发育缺陷或健康异常，B细胞和T细胞亚群的百分比也正常。CD40L缺陷小鼠在体液免疫中确实表现出选择性缺陷；基础血清同种型水平显著低于正常小鼠，且无法检测到IgE。此外，CD40L缺陷小鼠在用胸腺依赖性抗原三硝基苯酚偶联的钥孔戚血蓝蛋白（TNP-KLH）免疫后，未能产生二次抗原特异性反应。相比之下，CD40L缺陷小鼠在对胸腺非依赖性抗原DNP-Ficoll的反应中产生了除IgE之外的所有同种型的抗原特异性抗体。这些结果强调了CD40L对T细胞依赖性抗体反应的必要性。此外，在没有CD40L的情况下，体内也可以发生向除IgE之外的同种型的Ig类别转换，这支持了替代B细胞信号通路调节对胸腺非依赖性抗原反应的观点。
