Clonotypic analysis of protective influenza M2e-specific lung resident Th17 memory cells reveals extensive functional diversity

Omokanye, Ajibola; Ong, Li Ching; Lebrero‐Fernández, Cristina; Bernasconi, Valentina; Schön, Karin; Strömberg, Anneli; Bemark, Mats; Saelens, Xavier; Czarnewski, Paulo; Lycke, Nils

doi:10.1038/s41385-022-00497-9

Cited by 21 publications

(18 citation statements)

References 87 publications

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“…There is emerging evidence that mucosal CD4 + and CD8 + T cells contribute to a rapid and effective clearance of pulmonary pathogens with influenza A being the most investigated, prototypical example ( 14 – 16 , 61 ). The Varga lab dissected the role of T cell responses in RSV infections in a series of publications.…”

Section: Discussionmentioning

confidence: 99%

Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity

et al. 2022

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Respiratory syncytial virus (RSV) infections are the leading cause of severe respiratory illness in early infancy. Although the majority of children and adults mount immune responses against RSV, recurrent infections are frequent throughout life. Humoral and cellular responses contribute to an effective immunity but also their localization at respiratory mucosae is increasingly recognized as an important factor. In the present study, we evaluate a mucosal vaccine based on an adenoviral vector encoding for the RSV fusion protein (Ad-F), and we investigate two genetic adjuvant candidates that encode for Interleukin (IL)-1β and IFN-β promoter stimulator I (IPS-1), respectively. While vaccination with Ad-F alone was immunogenic, the inclusion of Ad-IL-1β increased F-specific mucosal immunoglobulin A (IgA) and tissue-resident memory T cells (TRM). Consequently, immunization with Ad-F led to some control of virus replication upon RSV infection, but Ad-F+Ad-IL-1β was the most effective vaccine strategy in limiting viral load and weight loss. Subsequently, we compared the Ad-F+Ad-IL-1β-induced immunity with that provoked by a primary RSV infection. Systemic F-specific antibody responses were higher in immunized than in previously infected mice. However, the primary infection provoked glycoprotein G-specific antibodies as well eventually leading to similar neutralization titers in both groups. In contrast, mucosal antibody levels were low after infection, whereas mucosal immunization raised robust F-specific responses including IgA. Similarly, vaccination generated F-specific TRM more efficiently compared to a primary RSV infection. Although the primary infection resulted in matrix protein 2 (M2)-specific T cells as well, they did not reach levels of F-specific immunity in the vaccinated group. Moreover, the infection-induced T cell response was less biased towards TRM compared to vaccine-induced immunity. Finally, our vaccine candidate provided superior protection against RSV infection compared to a primary infection as indicated by reduced weight loss, virus replication, and tissue damage. In conclusion, our mucosal vaccine candidate Ad-F+Ad-IL-1β elicits stronger mucosal immune responses and a more effective protection against RSV infection than natural immunity generated by a previous infection. Harnessing mucosal immune responses by next-generation vaccines is therefore a promising option to establish effective RSV immunity and thereby tackle a major cause of infant hospitalization.

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Section: Discussionmentioning

confidence: 99%

Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity

et al. 2022

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“…Influenza-specific CD4 + TRM cells characterize as Th1-like TRM cells secreting IFN-g and IL-2 and contribute to enhanced protection against influenza (15,34,115). Th1 TRM cells provide protection against influenza reinfection and influenza matrix protein ectodomain (M2e)-specific Th17 TRM cells are stimulated through intranasal immunization with M2e adjuvanted with CTA1-DD, generating strong protection against influenza (15,116). Conversely, in the BAL collected from patients with severe COVID-19, Th17 TRM cells persisted even after virus clearance.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary resident memory T cells in respiratory virus infection and their inspiration on therapeutic strategies

Zhang

et al. 2022

Front. Immunol.

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The immune system generates memory cells on infection with a virus for the first time. These memory cells play an essential role in protection against reinfection. Tissue-resident memory T (TRM) cells can be generated in situ once attacked by pathogens. TRM cells dominate the defense mechanism during early stages of reinfection and have gradually become one of the most popular focuses in recent years. Here, we mainly reviewed the development and regulation of various TRM cell signaling pathways in the respiratory tract. Moreover, we explored the protective roles of TRM cells in immune response against various respiratory viruses, such as Respiratory Syncytial Virus (RSV) and influenza. The complex roles of TRM cells against SARS-CoV-2 infection are also discussed. Current evidence supports the therapeutic strategies targeting TRM cells, providing more possibilities for treatment. Rational utilization of TRM cells for therapeutics is vital for defense against respiratory viruses.

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“…Further efforts are required to determine whether Tr1 cells contribute to tolerogenic memory in allergy models. In the context of influenza vaccination, a population of lung-resident memory Tr1 cells are induced and further expand upon re-challenge, though a protective role for Tr1 memory cells was not assessed as their presence was an unexpected finding ( 43 ). In other instances, a role for memory Tr1 cells in promoting tolerance has been demonstrated.…”

Section: Classification Of Tr1 Cells and Mechanisms Of Their Inductionmentioning

confidence: 99%

Type 1 regulatory T cell-mediated tolerance in health and disease

2022

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Type 1 regulatory T (Tr1) cells, in addition to other regulatory cells, contribute to immunological tolerance to prevent autoimmunity and excessive inflammation. Tr1 cells arise in the periphery upon antigen stimulation in the presence of tolerogenic antigen presenting cells and secrete large amounts of the immunosuppressive cytokine IL-10. The protective role of Tr1 cells in autoimmune diseases and inflammatory bowel disease has been well established, and this led to the exploration of this population as a potential cell therapy. On the other hand, the role of Tr1 cells in infectious disease is not well characterized, thus raising concern that these tolerogenic cells may cause general immune suppression which would prevent pathogen clearance. In this review, we summarize current literature surrounding Tr1-mediated tolerance and its role in health and disease settings including autoimmunity, inflammatory bowel disease, and infectious diseases.

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Clonotypic analysis of protective influenza M2e-specific lung resident Th17 memory cells reveals extensive functional diversity

Cited by 21 publications

References 87 publications

Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity

Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity

Pulmonary resident memory T cells in respiratory virus infection and their inspiration on therapeutic strategies

Type 1 regulatory T cell-mediated tolerance in health and disease

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