Ly6Chi monocytes orchestrate immune responses to respiratory viruses

A study conducted by researchers from the Department of Infectious Diseases at the University of Liège (ULiège / Belgium) has just highlighted the important role of Ly6C^hi monocytes in the regulation of immune responses in certain infectious diseases. This research opens new perspectives in the therapeutic management of various severe immunopathologies associated with respiratory viral infections.

Microorganisms are major environmental factors that play fundamental roles in the education and modulation of host immune responses. In particular, the interaction between pathogens and the host immune system is essential for the development of effective and well-regulated immunity. As respiratory viruses are in the news, considerable attention is devoted to ongoing research into the mechanisms of regulation of antiviral immune responses. The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) pandemic has highlighted the diversity of antiviral responses in the world population and the difference in sensitivity to the same pathogen, ranging from asymptomatic infection to fatal disease of the individual.

This diversity of immune responses between individuals could be due in particular to the exposure of the immune system to previous infections," explains Céline Maquet, Researcher in the Department of Infectious Diseases at ULiège. It is now established that the variation in the immune system depends more on environmental factors than on genetic factors. Among these environmental factors, exposure to infectious agents in childhood could shape the immune system and modulate subsequent immune responses when exposed to other microorganisms. While the influence of the microbiota has been widely investigated, researchers are now focusing on the modulation of the immune system by viruses. A better understanding of innate pathophysiological mechanisms is essential to identify targets for specific therapeutic interventions. Among the players of innate immunity, monocytes show remarkable plasticity and heterogeneity and have an important role in pathogen elimination, immunomodulation or maintenance of inflammation depending on the context. Understanding the balance between pro-inflammatory and immunomodulatory pathways triggered by monocytes during viral infections is therefore of major importance.

In the study we have just published in Science Immunology," explains Bénédicte Machiels, Research Associate at ULiège, "we were interested in the regulatory mechanisms induced by persistent viruses, gammaherpesviruses (γHVs) - extremely prevalent viruses in both humans and animals - that have co-evolved with their host for millions of years. The main characteristic of these viruses - which infect 80-90% of the human population - is their ability to induce a latent infection, which in most cases remains asymptomatic. Thus, these viruses have developed multiple immunomodulatory strategies ensuring a delicate balance between the inflammatory response necessary to control the pathogen and the maintenance of tissue homeostasis in the infected individual.

However, we have observed that in certain pathologies associated with gammaherpesvirus infections, this balance is disrupted and leads to the development of severe immunopathologies," explains Professor Laurent Gillet. Similarly, this balance between protective and deleterious responses is disrupted during infections by highly pathogenic respiratory viruses. To better understand what determines this state of equilibrium, we decided to investigate the immune players that regulate inflammation in the airways during infection by MuHV-4, a mouse gammaherpesvirus. In particular, we dissected the role of monocytes as key players in the regulation of the immune response.

This work has enabled ULiège researchers to demonstrate that pulmonary infection by MuHV-4 leads to the recruitment, in the airways, of Ly6C^hi monocytes capable of modulating the host immune response. Indeed, the absence of Ly6C^hi monocytes is associated with severe virus-induced immunopathology and the systemic release of pro-inflammatory mediators. "Mechanistically, virus-imprinted monocytes recruit CD4 T cells to the airways, some of which are regulatory T cells. At the same time, these monocytes initiate immunosuppressive signalling pathways via the PD-L1/PD-1 axis attenuating the deleterious activation of cytotoxic CD4 T cells," explains Céline Maquet. These results highlight the role of Ly6C^hi monocytes in the modulation of CD4 T cell functions and identify molecular pathways as potential therapeutic targets to reduce severe immunopathologies associated with respiratory viral infections. Indeed, CD4 T cells with cytotoxic functions are of increasing interest. Their presence in certain viral infections, including primary EBV infection, anti-tumour responses or autoimmune disorders, has been associated with either disease aggravation or induction of protective immunity. Regarding the ambivalent contribution of cytotoxic CD4 T cells to beneficial or pathogenic immune responses, understanding the regulatory pathways of these so-called "super killer" cells by monocytes is of major importance. "In summary, gammaherpesvirus-imprinted monocytes orchestrate the balance between cytotoxic and regulatory properties of CD4 T cells. Overall, this work has dissected the complex interaction between monocytes and CD4 T cells in the lung after infection with MuHV-4," concluded Céline Maquet. This study revealed the importance of IL-10 and PD-L1/PD-1 signalling in reducing the deleterious inflammation that protects against the development of severe respiratory damage and systemic diseases. This study could open new perspectives, beyond the context of gammaherpesvirus infections, in the therapeutic management of various viral immunopathologies.