白细胞介素9介导T滤泡辅助细胞活化以促进抗体反应
2024/10/29
摘要
抗原特异性体液反应是通过淋巴组织中免疫细胞之间的复杂相互作用来协调的，包括B细胞和T滤泡辅助细胞（Tfh）之间的协作。越来越多的证据表明，白细胞介素-9（IL-9）在生发中心（GC）的形成中起着至关重要的作用，可以增强类转换高亲和力抗体的产生。然而，IL-9在Tfh细胞调节中的确切作用尚不清楚。在这项研究中，我们检测了CD4Cre/+Il9rafl/fl小鼠的体液免疫反应，这些小鼠在Tfh细胞中缺乏IL-9特异性受体。在用绵羊红细胞（SRBC）进行腹腔免疫后，CD4Cre/+Il9rafl/fl小鼠血清中SRBC特异性IgG抗体水平降低，GC B细胞和浆细胞水平降低。值得注意的是，与对照组小鼠相比，脾脏中Il9ra缺陷型Tfh细胞的标志性分子如B细胞淋巴瘤6、C-X-C趋化因子受体5、IL-4和IL-21的表达降低。在吸入屋尘螨（HDM）诱导的过敏性哮喘模型中，CD4Cre/+Il9rafl/fl小鼠未能提高HDM特异性IgE和IgG的血清水平。这伴随着纵隔淋巴结中Tfh细胞、GC B细胞和浆细胞的减少。此外，在免疫条件下，第2组先天淋巴细胞（ILC2s）被鉴定为IL-9的产生者，这可能是由T-B边界周围活化的IgD B细胞释放的白三烯诱导的。这些观察结果可能表明IL-9受体信号传导在Tfh细胞活化中的关键作用，ILC2s可能能够在有组织的淋巴组织中提供IL-9+。
Interleukin 9 mediates T follicular helper cell activation to promote antibody responses
Taiki Sato, Ippei Ikegami, Masahiro Yanagi, Takeshi Ohyu, Taiki Sugaya, Shotaro Shirato, Masanobu Tanemoto, Shiori Kamiya, Kohei Kikuchi, Yuka Kamada, Takehito Nakata, Ryuta Kamekura, Akinori Sato, Ken-Ichi Takano, Masahiro Miyajima, Atsushi Watanabe, Shingo Ichimiya
Abstract
Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.
抗原特异性体液反应是通过淋巴组织中免疫细胞之间的复杂相互作用来协调的，包括B细胞和T滤泡辅助细胞（Tfh）之间的协作。越来越多的证据表明，白细胞介素-9（IL-9）在生发中心（GC）的形成中起着至关重要的作用，可以增强类转换高亲和力抗体的产生。然而，IL-9在Tfh细胞调节中的确切作用尚不清楚。在这项研究中，我们检测了CD4Cre/+Il9rafl/fl小鼠的体液免疫反应，这些小鼠在Tfh细胞中缺乏IL-9特异性受体。在用绵羊红细胞（SRBC）进行腹腔免疫后，CD4Cre/+Il9rafl/fl小鼠血清中SRBC特异性IgG抗体水平降低，GC B细胞和浆细胞水平降低。值得注意的是，与对照组小鼠相比，脾脏中Il9ra缺陷型Tfh细胞的标志性分子如B细胞淋巴瘤6、C-X-C趋化因子受体5、IL-4和IL-21的表达降低。在吸入屋尘螨（HDM）诱导的过敏性哮喘模型中，CD4Cre/+Il9rafl/fl小鼠未能提高HDM特异性IgE和IgG的血清水平。这伴随着纵隔淋巴结中Tfh细胞、GC B细胞和浆细胞的减少。此外，在免疫条件下，第2组先天淋巴细胞（ILC2s）被鉴定为IL-9的产生者，这可能是由T-B边界周围活化的IgD B细胞释放的白三烯诱导的。这些观察结果可能表明IL-9受体信号传导在Tfh细胞活化中的关键作用，ILC2s可能能够在有组织的淋巴组织中提供IL-9+。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Front Immunol. 2024 Sep 30:15:1441407. doi: 10.3389/fimmu.2024.1441407.)
(Front Immunol. 2024 Sep 30:15:1441407. doi: 10.3389/fimmu.2024.1441407.)
Interleukin 9 mediates T follicular helper cell activation to promote antibody responses
Taiki Sato, Ippei Ikegami, Masahiro Yanagi, Takeshi Ohyu, Taiki Sugaya, Shotaro Shirato, Masanobu Tanemoto, Shiori Kamiya, Kohei Kikuchi, Yuka Kamada, Takehito Nakata, Ryuta Kamekura, Akinori Sato, Ken-Ichi Takano, Masahiro Miyajima, Atsushi Watanabe, Shingo Ichimiya
Abstract
Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.
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