Immunity hubs orchestrating antiviral defense | Cell Research

Oct 17, 2024

Cell Research (2024)Cite this article

1 Altmetric

Metrics details

You have full access to this article via your institution.

Understanding the intricate dynamics of the immune response to SARS-CoV-2 is crucial for developing effective antiviral therapies. Two important studies published in Cell Discovery provide a detailed spatiotemporal map of the immune landscape in SARS-CoV-2-infected lungs, unveiling novel cellular hubs and their critical interplay with macrophages in orchestrating viral clearance and inflammation resolution.

The immune response to SARS-CoV-2 is a multi-stage process involving immune surveillance, activation, tissue damage, viral clearance, and tissue repair. Identifying the key cell subpopulations and their regulatory networks at each stage is essential for deciphering COVID-19 pathogenesis and developing antiviral therapies. While previous studies have identified key cell types at various stages of infection, no single study has provided a comprehensive overview spanning the entire process, from infection to inflammation resolution. Additionally, the lack of high-resolution spatiotemporal data has hindered the visualization of in situ immune cell coordination, which is crucial for viral clearance and inflammation resolution. Cong and colleagues recently published two back-to-back papers in Cell Discovery, presenting an organ-scale, high-resolution spatiotemporal single-cell atlas of the lung’s response to SARS-CoV-2 in a hamster model.1,2 These studies collectively provide a holistic overview, revealing novel mechanisms of viral clearance and immune homeostasis.

The authors meticulously collected lung samples from SARS-CoV-2-infected hamsters at five critical time points, which represent the entire process of infection: pre-infection (d0), acute tissue damage (d2), acute immune response (d5), viral clearance (d7), and inflammation resolution with tissue repair (d14). Employing spatial transcriptomics at a 500-nm resolution alongside single-cell RNA sequencing (scRNA-seq), they developed immunocartography — a high-resolution technique that combines spatial transcriptomics with scRNA-seq for spatial deconvolution3 and co-localization analysis. Through integrative analysis, the authors generated single-cell spatial transcriptomic profiles at various stages of infection, revealing the presence of the virus in multiple cell types, including epithelial and immune cells. These findings are consistent with those reported by Ren et al.4

The first study introduced a paradigm-shifting perspective on the initial immune response to SARS-CoV-2.1 By utilizing immunocartography, the authors generated a comprehensive map of the immune response in the Syrian hamsters infected with SARS-CoV-2. This map captured the dynamic interplay among various immune cells, particularly highlighting the formation of dendritic cell (DC)–T cell immunity hubs. These hubs, composed of Ccr7+Ido1+ DCs, Cd160+Cd8+ T cells, and Tnfrsf4+Cd4+ T cells, were found to rapidly expand upon infection, by recruiting various immune cell types, particularly Slamf9+ macrophages to defend against the virus.

The second study extended this finding to the later stages of the immune response.2 The authors identified Slamf9+ macrophages as a novel cell population induced during SARS-CoV-2 infection. These monocyte-derived Slamf9+ macrophages, distinct from tissue-resident alveolar macrophages, could clear the virus by recruiting and interacting with Isg12+Cst7+ neutrophils. At the later stages of infection, Slamf9+ macrophages differentiated into Trem2+ and Fbp1+ macrophages to resolve inflammation and repair damaged lung tissue. These findings were validated in both human ACE2-transgenic mouse models and autopsy samples from SARS-CoV-2 patients, further highlighting the role of these macrophages in post-injury lung repair. This discovery sheds light on the macrophages’ multifaceted roles in the immune response to SARS-CoV-2, underscoring their importance in both acute and recovery phases of infection.

In summary, these two studies offer profound theoretical and clinical insights. They provide a comprehensive cellular and molecular atlas of the lung, spanning from infection to tissue homeostasis restoration (Fig. 1). This atlas serves as an invaluable resource for studying lung immune responses. The identification of novel Cd160+Cd8+ T cell subsets within alveolar DC–T immunity hubs in normal hamster lungs, which respond as early as two days post SARS-CoV-2 infection, enriches our understanding of the immune response timeline. In a typical antiviral immune response, antigen-presenting cells capture pathogens and migrate to nearby lymph nodes, where they activate naïve T cells, leading to their proliferation, differentiation into effector T cells, and migration to the site of infection — a process that takes about a week.5 As a significant contribution, these studies reveal pre-existing DC–T immunity hubs in healthy lung tissue, which may act as sentinels to ensure rapid immune responses to viral infections, thereby saving critical time for the body to control the infection. In addition, the DC–T immunity hubs discovered in SARS-CoV-2 infection were also found in tumors, where they played a role in promoting anti-tumor immunity and enhancing the effects of immunotherapy. Chen et al.6 utilized spatial profiling techniques on lung cancer samples and identified stem–immunity hubs containing mature regulatory DCs (mregDCs), Tcf7+Cd4+ T cells, Tcf7+Cd8+ T cells, and Ccl19+ fibroblasts, which were associated with positive outcomes in immunotherapy. Espinosa-Carrasco et al.7 discovered that the spatial colocalization of Cd4+ T cells, Cd8+ T cells, and DCs formed a three-cell cluster (triad), which enabled Cd8+ T cell cytotoxicity and cancer cell elimination. Interestingly, the Ccr7+Ido1+ DCs found in the DC–T immunity hubs during SARS-CoV-2 infection show significant transcriptomic similarity to the Ccr7+Lamp3+Ido1+Cd274+ activated DCs (Lamp3+ DCs) identified by Zhang et al. in hepatocellular carcinoma,8 which play crucial roles in response to PD-1 blockade therapy. The transcriptomic features of mregDCs are also very similar to those of Lamp3+ DCs, suggesting that immunity hubs may share common formation mechanisms in both infections and tumors, hinting at their broader role in immune surveillance. These findings pave the way for targeted therapeutic strategies that could harness the power of these DC–T immunity hubs to combat SARS-CoV-2 and tumors.

Before SARS-CoV-2 infection (①), Cd160+Cd8+ T cells, Tnfrsf4+Cd4+ T cells, and Ccr7+Ido1+ DCs form DC–T immunity hubs. Upon infection, monocyte-derived Slamf9+ macrophages are recruited by these hubs during acute tissue damage (②). These macrophages further recruit Isg12+Cst7+ neutrophils (③), which ultimately work together to clear the virus (④). After viral clearance, Slamf9+ macrophages transition into Trem2+ and Fbp1+ macrophages to resolve inflammation and aid in tissue repair (⑤). Figure created with BioRender.com.

Cong, B. et al. Cell Discov. https://doi.org/10.1038/s41421-024-00733-5 (2024).

Article PubMed PubMed Central Google Scholar

Cong, B. et al. Cell Discov. https://doi.org/10.1038/s41421-024-00734-4 (2024).

Article PubMed PubMed Central Google Scholar

Zhou, Z., Zhong, Y., Zhang, Z. & Ren, X. Nat. Commun. 14, 7930 (2023).

Article CAS PubMed PubMed Central Google Scholar

Ren, X. et al. Cell 184, 1895–1913.e19 (2021).

Article CAS PubMed PubMed Central Google Scholar

Moss, P. Nat. Immunol. 23, 186–193 (2022).

Article CAS PubMed Google Scholar

Chen, J. H. et al. Nat. Immunol. 25, 644–658 (2024).

Article CAS PubMed Google Scholar

Espinosa-Carrasco, G. et al. Cancer Cell 42, 1202–1216.e8 (2024).

Article CAS PubMed Google Scholar

Zhang, Q. et al. Cell 179, 829–845.e20 (2019).

Article CAS PubMed Google Scholar

Download references

Biomedical Pioneering Innovation Center (BIOPIC), and School of Life Sciences, Peking University, Beijing, China

Linnan Zhu & Zemin Zhang

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

Correspondence to Linnan Zhu or Zemin Zhang.

The authors declare no competing interests.

Reprints and permissions

Zhu, L., Zhang, Z. Immunity hubs orchestrating antiviral defense. Cell Res (2024). https://doi.org/10.1038/s41422-024-01036-w

Download citation

Published: 16 October 2024

DOI: https://doi.org/10.1038/s41422-024-01036-w

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative