Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.
Front Immunol. 2023 Feb 21;13:1041552. doi: 10.3389/fimmu.2022.1041552. eCollection 2022.
αLβ2 (LFA-1) mediated interactions with ICAM-1 and ICAM-2 predominate leukocyte-vascular interactions, but their functions in extravascular cell-cell communications is still debated. The roles of these two ligands in leukocyte trafficking, lymphocyte differentiation, and immunity to influenza infections were dissected in the present study. Surprisingly, double ICAM-1 and ICAM-2 knock out mice (herein ICAM-1/2 mice) infected with a lab adapted H1N1 influenza A virus fully recovered from infection, elicited potent humoral immunity, and generated normal long lasting anti-viral CD8 T cell memory. Furthermore, lung capillary ICAMs were dispensable for both NK and neutrophil entry to virus infected lungs. Mediastinal lymph nodes (MedLNs) of ICAM-1/2 mice poorly recruited naïve T cells and B lymphocytes but elicited normal humoral immunity critical for viral clearance and effective CD8 differentiation into IFN-γ producing T cells. Furthermore, whereas reduced numbers of virus specific effector CD8 T cells accumulated inside infected ICAM-1/2 lungs, normal virus-specific T CD8 cells were generated inside these lungs and fully protected ICAM-1/2 mice from secondary heterosubtypic infections. B lymphocyte entry to the MedLNs and differentiation into extrafollicular plasmablasts, producing high affinity anti-influenza IgG2a antibodies, were also ICAM-1 and ICAM-2 independent. A potent antiviral humoral response was associated with accumulation of hyper-stimulated cDC2s in ICAM null MedLNs and higher numbers of virus-specific T follicular helper (Tfh) cells generated following lung infection. Mice selectively depleted of cDC ICAM-1 expression supported, however, normal CTL and Tfh differentiation following influenza infection, ruling out essential co-stimulatory functions of DC ICAM-1 in CD8 and CD4 T cell differentiation. Collectively our findings suggest that lung ICAMs are dispensable for innate leukocyte trafficking to influenza infected lungs, for the generation of peri-epithelial T CD8 cells, and long term anti-viral cellular immunity. In lung draining LNs, although ICAMs promote lymphocyte homing, these key integrin ligands are not required for influenza-specific humoral immunity or generation of IFN-γ effector CD8 T cells. In conclusion, our findings suggest unexpected compensatory mechanisms that orchestrate protective anti-influenza immunity in the absence of vascular and extravascular ICAMs.
αLβ2（LFA-1）与 ICAM-1 和 ICAM-2 的相互作用在白细胞与血管的相互作用中占主导地位，但它们在血管外细胞间通讯中的功能仍存在争议。本研究探讨了这两种配体在白细胞迁移、淋巴细胞分化和对流感感染的免疫中的作用。令人惊讶的是，双重 ICAM-1 和 ICAM-2 敲除小鼠（简称 ICAM-1/2 小鼠）感染实验室适应的 H1N1 流感 A 病毒后完全从感染中恢复，产生了强大的体液免疫，并产生了正常的长效抗病毒 CD8 T 细胞记忆。此外，肺毛细血管 ICAMs 对于 NK 和中性粒细胞进入病毒感染的肺均不是必需的。ICAM-1/2 小鼠的纵隔淋巴结（MedLNs）很少招募幼稚 T 细胞和 B 淋巴细胞，但产生了清除病毒和有效分化 CD8 为 IFN-γ 产生 T 细胞所必需的正常体液免疫。此外，虽然在感染的 ICAM-1/2 肺中积累的病毒特异性效应 CD8 T 细胞数量减少，但在这些肺中仍能产生正常的病毒特异性 CD8 T 细胞，并完全保护 ICAM-1/2 小鼠免受二次异源感染。B 淋巴细胞进入 MedLNs 并分化为滤泡外浆母细胞，产生高亲和力的抗流感 IgG2a 抗体，也与 ICAM-1 和 ICAM-2 无关。强烈的抗病毒体液反应与 ICAM 缺失的 MedLNs 中过度刺激的 cDC2s 的积累以及肺感染后产生的更多病毒特异性 T 滤泡辅助（Tfh）细胞有关。然而，选择性耗尽 cDC ICAM-1 表达的小鼠支持流感感染后 CTL 和 Tfh 的正常分化，排除了 DC ICAM-1 在 CD8 和 CD4 T 细胞分化中的重要共刺激功能。总的来说，我们的发现表明肺 ICAMs 对于先天白细胞向流感感染肺的迁移、上皮周围 T CD8 细胞的产生以及长期抗病毒细胞免疫是可有可无的。在肺引流的 LNs 中，尽管 ICAMs 促进淋巴细胞归巢，但这些关键整合素配体对于流感特异性体液免疫或 IFN-γ 效应 CD8 T 细胞的产生并不是必需的。总之，我们的发现表明，在没有血管和血管外 ICAMs 的情况下，存在着协调保护性抗流感免疫的意外代偿机制。
