Lee Peishan, Zhu Zilu, Hachmann Janna, Nojima Takuya, Kitamura Daisuke, Salvesen Guy, Rickert Robert C
Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92037.
J Immunol. 2017 Feb 1;198(3):1066-1080. doi: 10.4049/jimmunol.1502518. Epub 2016 Dec 28.
During a T cell-dependent immune response, formation of the germinal center (GC) is essential for the generation of high-affinity plasma cells and memory B cells. The canonical NF-κB pathway has been implicated in the initiation of GC reaction, and defects in this pathway have been linked to immune deficiencies. The paracaspase MALT1 plays an important role in regulating NF-κB activation upon triggering of Ag receptors. Although previous studies have reported that MALT1 deficiency abrogates the GC response, the relative contribution of B cells and T cells to the defective phenotype remains unclear. We used chimeric mouse models to demonstrate that MALT1 function is required in B cells for GC formation. This role is restricted to BCR signaling where MALT1 is critical for B cell proliferation and survival. Moreover, the proapoptotic signal transmitted in the absence of MALT1 is dominant to the prosurvival effects of T cell-derived stimuli. In addition to GC B cell differentiation, MALT1 is required for plasma cell differentiation, but not mitogenic responses. Lastly, we show that ectopic expression of Bcl-2 can partially rescue the GC phenotype in MALT1-deficient animals by prolonging the lifespan of BCR-activated B cells, but plasma cell differentiation and Ab production remain defective. Thus, our data uncover previously unappreciated aspects of MALT1 function in B cells and highlight its importance in humoral immunity.
在T细胞依赖性免疫反应过程中，生发中心（GC）的形成对于高亲和力浆细胞和记忆B细胞的产生至关重要。经典的核因子κB（NF-κB）信号通路与GC反应的启动有关，该信号通路的缺陷与免疫缺陷相关。副半胱天冬酶MALT1在抗原受体触发后调节NF-κB激活中发挥重要作用。尽管先前的研究报道MALT1缺陷会消除GC反应，但B细胞和T细胞对缺陷表型的相对贡献仍不清楚。我们使用嵌合小鼠模型证明，B细胞中需要MALT1功能来形成GC。该作用仅限于BCR信号传导，其中MALT1对B细胞增殖和存活至关重要。此外，在没有MALT1的情况下传递的促凋亡信号对T细胞衍生刺激的促存活作用具有主导性。除了GC B细胞分化外，浆细胞分化也需要MALT1，但丝裂原反应则不需要。最后，我们表明，Bcl-2的异位表达可以通过延长BCR激活的B细胞寿命来部分挽救MALT1缺陷动物的GC表型，但浆细胞分化和抗体产生仍然存在缺陷。因此，我们的数据揭示了B细胞中MALT1功能以前未被认识的方面，并突出了其在体液免疫中的重要性。
