Glickman Urological Institute and Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Service de Transplantation Rénale, Hôpital Necker, 75743 Paris Cedex 15, France.
Am J Transplant. 2013 Nov;13(11):2831-2841. doi: 10.1111/ajt.12432. Epub 2013 Sep 18.
CD40/CD154 interactions are essential for productive antibody responses to T-dependent antigens. Memory CD4 T cells express accelerated helper functions and are less dependent on costimulation when compared with naïve T cells. Here, we report that donor-reactive memory CD4 T cells can deliver help to CD40-deficient B cells and induce high titers of IgG alloantibodies that contribute to heart allograft rejection in CD40-/- heart recipients. While cognate interactions between memory helper T and B cells are crucial for CD40-independent help, this process is not accompanied by germinal center formation and occurs despite inducible costimulatory blockade. Consistent with the extrafollicular nature of T/B cell interactions, CD40-independent help fails to maintain stable levels of serum alloantibody and induce differentiation of long-lived plasma cells and memory B cells. In summary, our data suggest that while CD40-independent help by memory CD4 T cells is sufficient to induce high levels of pathogenic alloantibody, it does not sustain long-lasting anti-donor humoral immunity and B cell memory responses. This information may guide the future use of CD40/CD154 targeting therapies in transplant recipients containing donor-reactive memory T cells.
CD40/CD154 相互作用对于 T 依赖性抗原的有效抗体反应至关重要。与初始 T 细胞相比，记忆 CD4 T 细胞表达加速的辅助功能，并且对共刺激的依赖性降低。在这里，我们报告供体反应性记忆 CD4 T 细胞可以向 CD40 缺陷 B 细胞提供帮助，并诱导高水平的 IgG 同种抗体，导致 CD40-/-心脏受者的心脏移植物排斥。虽然记忆辅助 T 和 B 细胞之间的同源相互作用对于 CD40 非依赖性帮助至关重要，但这个过程不会伴随生发中心的形成，并且即使存在可诱导的共刺激阻断也会发生。与 T/B 细胞相互作用的滤泡外性质一致，CD40 非依赖性帮助无法维持稳定的血清同种抗体水平，并诱导长寿浆细胞和记忆 B 细胞的分化。总之，我们的数据表明，虽然记忆 CD4 T 细胞的 CD40 非依赖性帮助足以诱导高水平的致病性同种抗体，但它不能维持持久的抗供体体液免疫和 B 细胞记忆反应。这些信息可能指导未来在含有供体反应性记忆 T 细胞的移植受者中使用 CD40/CD154 靶向治疗。
