Role of the stroma-derived ‘alarmin’ IL-33 in anti-viral immunity

Informazioni relative al progetto

STRAVIR

ID dell’accordo di sovvenzione: 708715

DOI

10.3030/708715

Progetto chiuso

Data della firma CE 11 Marzo 2016

Data di avvio 1 Ottobre 2016

Data di completamento 30 Settembre 2018

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 175 419,60

Contributo UE

€ 175 419,60

Coordinato da

UNIVERSITE DE LAUSANNE
Switzerland

Periodic Reporting for period 1 - STRAVIR (Role of the stroma-derived ‘alarmin’ IL-33 in anti-viral immunity)

Periodo di rendicontazione: 2016-10-01 al 2018-09-30

Sintesi del contesto e degli obiettivi generali del progetto

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

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.

Model: Fibroblastic reticular cells (FRC)-derived IL-33 boosts anti-viral immunity