Countless new infections occur around the world every day, and a significant portion of sexually active people are likely to contract a sexually transmitted infection before the age of 25. Viral infections such as Zika, dengue, mpox, herpes simplex virus (HSV) and human immunodeficiency. The virus (HIV) usually enters the body through the skin and mucous membranes. The best defense against these infections is vaccination. However, to design effective vaccines, it is essential to understand the immune cells in these tissues and how they interact with these viruses. Recent research has shed light on the complex functions of these cells, which could lead to significant advances in vaccine development.
Researchers at the University of Sydney's Westmead Institute of Medical Research, led by Professor Andrew Harman, have made significant progress in understanding the immune cells that inhabit the stratified squamous epithelium (SSE) of the skin and mucosa. The team, which includes Erica Vine, Dr Kirstie Bertram, Associate Professor Paul Austin, Dr Thomas O'Neil, Dr Najla Nasr and Professor Anthony Cunningham, has published their findings in the journals Nature Communications, PLoS Pathogens, Immunity and, most recently, Cell Reports. , offering new insights that could revolutionize mucosal vaccine design.
The SSE, which forms the outermost layer of the skin and certain mucosal tissues, is a critical barrier against pathogens. Historically, Langerhans cells (LCs) were considered the only antigen-presenting cells (APCs) within the SSE. However, recent research has identified another key player: dendritic cells (DCs). These findings have profound implications for the development of next-generation vaccines targeting skin and mucosal surfaces.
Professor Harman explained: “Our research highlights the distinct roles of LC and DC cells in pathogen uptake and immune activation. “This distinction is crucial to designing vaccines that can effectively utilize the unique capabilities of these cells.” The study highlights the importance of correctly identifying and characterizing these APCs to improve vaccine efficacy.
One of the key revelations of the study is the functional differences between LC and DC. While both cell types are involved in pathogen detection and processing, they exhibit different mechanisms for pathogen uptake and T cell activation. In particular, DCs have been shown to be more effective in certain immune responses, although still Its role in neuroimmune interactions is not fully understood.
The implications of these findings are particularly relevant for mucosal vaccines, which aim to induce immunity at sites of pathogen entry, such as the genital and respiratory tracts. Since sexually transmitted infections (STIs) and other viral infections such as mpox, herpes simplex virus (HSV), and human immunodeficiency virus (HIV) often enter the body through these routes, optimizing delivery of vaccines to these areas is essential.
The research team has also highlighted the historical evolution of our understanding of APCs in the SSE. Initially, LCs were the main focus, but the identification of epithelial DCs has expanded the landscape of immune defense mechanisms in these tissues. This evolution underscores the dynamic nature of immunological research and the continuous need to update our knowledge base with new findings.
Professor Harman said: “The identification of developing countries in the EES opens new avenues for vaccine development. “By taking advantage of the unique properties of these cells, we can design more specific and effective vaccines that provide robust protection against a variety of pathogens.” This approach could be particularly beneficial for creating vaccines that elicit strong local immune responses at the site of infection.
Furthermore, the study sheds light on neuroimmune interactions within SES. The presence of nerve endings that interact with immune cells suggests a complex interaction that influences immune responses. Associate Professor Austin commented: “We are only at the beginning of unraveling these two-way interactions, and they represent a new and untapped frontier in vaccinology.” Understanding these interactions may contribute to the development of vaccines and therapies that modulate immune activity through neuronal pathways.
In conclusion, the research conducted by Professor Harman and colleagues marks a significant advance in our understanding of the immunological landscape within SES. By delineating the functions of LCs and DCs, this study provides a basis for the development of more effective mucosal vaccines. As the global community continues to combat infectious diseases, these innovations are essential to improving public health outcomes.
Magazine reference
Vine, EE, Austin, PJ, O'Neil, TR, Nasr, N., Bertram, KM, Cunningham, AL, and Harman, AN (2024). Epithelial dendritic cells versus Langerhans cells: implications for mucosal vaccines. Cell Reports, 43. DOI: https://doi.org/10.1016/j.celrep.2024.113977
Another reference
Bertram KM, Botting RA, Baharlou B, Rhodes JW, Rana H, Graham JD, Patrick E, Fletcher J, Plasto TM, Truong NR, Royle C, Doyle CM, Tong O, Nasr N, Barnouti L, Kohout MP, Brooks AJ , Wines MP, Haertsch P, Lim J, Gosselink MP, Ctercteko G, Estes JD, Churchill MJ, Cameron PU, Hunter E Haniffa MA, Cunningham AL, Harman AN. Identification of HIV-transmitting CD11c+ human epidermal dendritic cells Nature Communications 2019 PMID: 31227717.
Bertram KM, Truong NR, Smith JB, Kim M, Sandgren KJ, Feng KL, Herbert J, Rana H, Danastas K, Miranda M, Rhodes JW, Patrick E, Cohen RC, Lim J, Merten S, Harman AN*, Cunningham ALABAMA*. Herpes simplex virus type 1 infects Langerhans cells and the new epidermal dendritic cell, Epi-cDC2, through different entry pathways PLOS Pathogens 2021. PMID: 33905459. *same last author
Bertram KM, O'Neil TR, Vine EE, Baharlou H, Cunningham AL, Harman AN. Defining the landscape of human epidermal mononuclear phagocytes. Immunity 2023. PMID: 36921567.
About the Author
Andrew Harman He completed his PhD at the University of Cambridge studying how the herpes simplex virus enters cells and establishes an epidermal infection. He moved to Westmead Health Precinct in 2002 and is now Professor of Virology and Immunology in the Faculty of Medical Sciences at the University of Sydney and co-director of the Virus Research Center at the Westmead Institute of Medical Research. He has fostered partnerships with more than 30 physicians, making him unique globally in his privileged access to a wide range of human tissues freshly discarded from surgery, affected by a variety of diseases. He has two NHMRC Ideas grants as CIA, which fund his two research groups investigating the sexual transmission of HIV and inflammatory bowel disease. Importantly, he has identified new populations of dendritic cells inhabiting the stratified squamous epithelium in addition to Langerhans cells.
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