Periodic Reporting for period 1 - STRAVIR (Role of the stroma-derived ‘alarmin’ IL-33 in anti-viral immunity)
Reporting period: 2016-10-01 to 2018-09-30
Our immune system has evolved sophisticated mechanisms to defend our body against harmful infections produced by various pathogens including bacteria and viruses. Upon viral infection, stressed or damaged cells can release alarmins like interleukin-33 (IL-33) that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from a non-hematopoietic source has been identified as important factor driving anti-viral CD8+ T cell expansion, however the cell type producing it and the signals leading to their release are still poorly known. This project aims to identify and characterize the cellular source of IL-33, to eventually gain a better understanding of the mechanisms regulating protective immune responses to viruses. To this end, the research focused on the following objectives:
• Objective 1: Identification and characterization of IL-33 producing cells in secondary lymphoid organs during viral infection.
• Objective 2: Identification of the time window and signals regulating IL-33 production and secretion from the relevant stromal cells found in infected secondary lymphoid organs
• Objective 3: Characterization of the effects of IL-33 on the expansion, migration and function of virus-specific T cells
• Objective 1: Identification and characterization of IL-33 producing cells in secondary lymphoid organs during viral infection.
• Objective 2: Identification of the time window and signals regulating IL-33 production and secretion from the relevant stromal cells found in infected secondary lymphoid organs
• Objective 3: Characterization of the effects of IL-33 on the expansion, migration and function of virus-specific T cells
We have studied the role of various stromal cells of secondary lymphoid organs in IL-33 driven T cell responses to viral infection. We have used in vivo mouse models to identify the critical cellular sources of IL-33 as well as their contribution in regulating CD8 T cell function. Using IL-33 reporter mice, we identified fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL-33 sources in lymph nodes (LN) of naïve and virus-infected mice, both within the T zone and the medulla. During infection with lymphocytic choriomeningitis virus (LCMV) clone 13, these stromal cells lose most IL-33 expression presumably due to release thereby boosting the antiviral T cell response. Using mice lacking IL-33 selectively in FRC versus LEC we identify T zone FRC as the key IL-33 source driving the expansion and function of antiviral CD8+ T cells. Collectively, these findings show that LN FRC not only regulate the homeostasis and priming of T cells but also their expansion and effector cell differentiation.
The research results have been and will be shared with the scientific community by the following means:
• Publications of scientific articles: a manuscript is in preparation (close to being submitted).
• Conferences / Congresses: attendance to national and international scientific meetings, where I have presented the data with poster presentations.
• Seminars / symposiums: I have presented my research in seminars and symposiums, inside and outside my research center.
The research results have been and will be shared with the scientific community by the following means:
• Publications of scientific articles: a manuscript is in preparation (close to being submitted).
• Conferences / Congresses: attendance to national and international scientific meetings, where I have presented the data with poster presentations.
• Seminars / symposiums: I have presented my research in seminars and symposiums, inside and outside my research center.
The identification and characterization of the cells expressing IL-33 during viral infection, as well as the mechanisms regulating its secretion are of great interest to the immunology and medical community. The results we have obtained over the past 2 years clearly advance our knowledge of IL-33 biology during antiviral T cell immunity, and will allow us now to focus on FRC for a more detailed analysis of the release mechanism. We will also use these mouse models now for other disease settings such as graft versus host disease (GVHD) where IL-33 expression is critical. Collectively, our findings suggest that triggering the release of IL-33 from FRC may be a good strategy to enhance beneficial T cell responses to infectious agents, while inhibiting IL-33 release or function may be helpful in settings of pathogenic T cell responses such as in GVHD.