Impaired antigen‐specific lymphocyte priming in mice after Toll‐like receptor 4 activation via induction of monocytic myeloid‐derived suppressor cells
Impaired antigen‐specific lymphocyte priming in mice after Toll‐like receptor 4 activation via induction of monocytic myeloid‐derived suppressor cells
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DOI：
10.1002/eji.201847805
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发表时间：
2019-02
影响因子：
5.4
通讯作者：
H. Tsukamoto;Sao Kozakai;Yohei Kobayashi;Risako Takanashi;T. Aoyagi;M. Numasaki;S. Ohta;Y. Tomioka
中科院分区：
文献类型：
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作者：
H. Tsukamoto;Sao Kozakai;Yohei Kobayashi;Risako Takanashi;T. Aoyagi;M. Numasaki;S. Ohta;Y. Tomioka
在脓毒症中，病理包括从促炎状态向免疫抑制阶段的转变。我们先前的研究表明，激动型抗TLR4抗体可诱导长期的内毒素耐受，并抑制抗原特异性二次免疫球蛋白的产生。这些发现使我们推测，TLR4诱导的先天性耐受是由于原发感染导致的脓毒症的免疫抑制病理。因此，我们对TLR4抗体损伤抗原特异性体液免疫的机制进行了研究。在小鼠模型中，我们发现在TLR4抗体诱导的耐受小鼠中，初级抗原特异的免疫球蛋白G反应受损，这是抗原特异的GC B细胞和浆细胞数量减少的结果。TLR4抗体注射的OT-I和-II转基因小鼠的卵清蛋白特异性的CD4和CD8 T细胞应答在体外受到损害。过继转移研究表明，体内TLR4抗体抑制了OVA特异性的CD4和CD8T细胞反应。TLR4抗体诱导Gr1+CD11b+髓系抑制细胞(MDSC)扩增并抑制T细胞活化。与粒细胞MDSCs相比，单核细胞MDSCs对PD-L1和诱导型一氧化氮合酶的表达有更强的抑制作用。总之，TLR4激活所产生的免疫耐受诱导了单核细胞MDSCs的扩张，从而损害了抗原特异性T细胞的启动和免疫球蛋白的产生。
In sepsis, the pathology involves a shift from a proinflammatory state toward an immunosuppressive phase. We previously showed that an agonistic anti‐TLR4 antibody induced long‐term endotoxin tolerance and suppressed antigen‐specific secondary IgG production when primed prior to immunization with antigen. These findings led us to speculate that TLR4‐induced innate tolerance due to primary infection causes an immunosuppressive pathology in sepsis. Therefore, the mechanism underlying impaired antigen‐specific humoral immunity by the TLR4 antibody was investigated. We showed, in a mouse model, that primary antigen‐specific IgG responses were impaired in TLR4 antibody‐induced tolerized mice, which was the result of reduced numbers of antigen‐specific GC B cells and plasma cells. Ovalbumin‐specific CD4 and CD8 T‐cell responses were impaired in TLR4 antibody‐injected OT‐I and ‐II transgenic mice ex vivo. Adoptive transfer studies demonstrated suppression of OVA‐specific CD4 and CD8 T‐cell responses by the TLR4 antibody in vivo. The TLR4 antibody induced Gr1+CD11b+ myeloid‐derived suppressor cell (MDSC) expansion with suppression of T‐cell activation. Monocytic MDSCs were more suppressive and exhibited higher expression of PD‐L1 and inducible nitric oxidase compared with granulocytic MDSCs. In conclusion, immune tolerance conferred by TLR4 activation induces the expansion of monocytic MDSCs, which impairs antigen‐specific T‐cell priming and IgG production.