Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI) IRCCS San Raffaele Scientific Institute, Milan, Italy.
Pediatrics Clinic and Institute of Molecular Medicine A. Novicelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili of Brescia, Brescia, Italy.
Clin Immunol. 2020 Jan;210:108309. doi: 10.1016/j.clim.2019.108309. Epub 2019 Nov 18.
Mutations affecting the non-canonical pathway of NF-κB were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5, and CXCR5 Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFNγ, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets.
最近发现，影响 NF-κB 非经典途径的突变是一种与自身免疫强烈相关的常见可变免疫缺陷的基础。虽然内在 B 细胞异常解释了这种疾病的大部分体液缺陷，但关于 NFKB2 对滤泡辅助（Tfh）和调节（Treg）T 细胞的影响的详细数据很少。在这里，我们表明，杂合截断突变 NFKB2 的患者中 Tfh、CXCR5 和 CXCR5 Treg 细胞亚群显著减少。血浆 CXCL13 水平降低，强调了 NFKB2 在调节生发中心（GC）反应中的重要作用。突变患者的 CD4 T 细胞产生的促炎 IFNγ、IL-17 和 IL-10 细胞因子减少，但 IL-4 和 IL-21 的产生没有改变。总之，我们的研究结果表明，NFKB2 通过影响不仅 B 细胞而且 GC 相关 T 细胞亚群，影响人类 GC 反应的质量和效率。
