The traditional perception of mast cells (MC) was dominated for decades by their notorious property to initiate IgE-dependent allergic reactions. However, it is increasingly being appreciated that MC are an integral part of innate immunity, based mainly on their aptitude to rapidly initiate acute inflammatory reactions in the absence of IgE antibodies. Furthermore, their ability to cross-talk with cells from both the innate and adaptive arms of the immune system defines MC as "inbetweeners". Yet, the roles of MC in immunity against viral infections is far from being understood.
Herein, the applicants wish to intensify their successful cooperation on the role of MC to combat cytomegalovirus (CMV) infection in the well established animal model of murine cytomegalovirus (mCMV) infection. Closely related to human CMV, mCMV opens the opportunity to study clinically relevant models of CMV disease in the natural host. Exploratory work done by the applicants already revealed a critical role for MC in attracting protective CD8 T cells to the lungs, a known predilection site in acute CMV infections. In the present proposal, the mechanism(s) of mCMV-induced MC activation and degranulation as well as important MC-derived mediators able to orchestrate the antiviral response will be identified. Especially the hypothesis that viral gene products deliver the activation signal upon direct infection of MC will be further pursued.
CMV disease, including interstitial pneumonia, is still of major concern in immuno-compromised patients following hematopoietic (stem) cell transplantation (HCT) and can be mimicked and investigated using murine models. Syngeneic HCT with MC-deficient mice and congenic MC-sufficient littermates will allow to study the roles of donor- and recipient-derived MC on antiviral CD8 T cell functions and to identify the critical MC-derived mediators involved. As a further approximation to clinical HCT, the basic syngeneic model will be supplemented by MHC-matched allogeneic HCT using mouse strains with minor histocompatibility antigen (minor-HAg) mismatches. These allogeneic settings will enable the applicants to study the superimposition of MC functions in graft-versus-host disease and mCMV disease in a clinically relevant model.
(cooperation with AG Stassen, Institute for Immunology)