Prof. Dr. Thomas Winkler

Adaptive immune responses of γδ T cells in murine cytomegalovirus infections

The human cytomegalovirus (HCMV) is the leading viral cause of morbidity in immune compromised patients and perinatal pathology in newborns. There are no CMV specific vaccines available and antiviral chemotherapy results in considerable side effects and frequently induces drug resistance. Our previous published findings in mice infected with mouse CMV (MCMV) provide clear evidence that γδ T cells control acute CMV infections, particularly when conventional adaptive immune mechanisms are insufficient. Several characteristics of the γδ T cell response showed features of adaptive immune responses. Recently, in patients after allogeneic stem cell transplantation adaptive expansions of γδ T cells in response to HCMV reactivation have also been shown. These findings suggest similar mechanisms of viral immune surveillance to cytomegalovirus by γδ T cells in humans and in mice and encourage the development of new therapeutic concepts. We therefore want to use the MCMV infection model to answer important questions regarding the biology of γδ T cells in adaptive-like immune responses. For this purpose, we created for the first time a transgenic mouse model in which a defined TCRδ chain is inserted into the TCRδ locus. The inserted TCRδ chain was isolated from the immune response against MCMV. With the help of such a δTCR transgenic mice we will to study migration, proliferation, effector functions and establishment of memory of γδ T cells during MCMV infection. This project is part of the application for a Research Group FOR2799 “Receiving and Translating Signals via the γδ T Cell Receptor” and the project will benefit from the interactions with the other groups within the FOR2799 which are specified in the application.

Adaptive immune responses of γδ T cells in murine cytomegalovirus infections  

The human cytomegalovirus (HCMV) is the leading viral cause of morbidity in immune compromised patients and perinatal pathology in newborns. There are no CMV specific vaccines available and antiviral chemotherapy results in considerable side effects and frequently induces drug resistance. Our previous published findings in mice infected with mouse CMV (MCMV) provide clear evidence that γδ T cells control acute CMV infections, particularly when conventional adaptive immune mechanisms are insufficient. Several characteristics of the γδ T cell response showed features of adaptive immune responses. Recently, in patients after allogeneic stem cell transplantation adaptive expansions of γδ T cells in response to HCMV reactivation have also been shown. These findings suggest similar mechanisms of viral immune surveillance to cytomegalovirus by γδ T cells in humans and in mice and encourage the development of new therapeutic concepts.We therefore want to use the MCMV infection model to answer important questions regarding the biology of γδ T cells in adaptive-like immune responses. For this purpose, we intent to create a transgenic mouse model with a defined γδ T-cell receptor (γδ TCR) that we isolated from the immune response against MCMV in several mice. With the help of such γδ TCR transgenic mice we intend to study migration, proliferation, effector functions and establishment of memory of γδ T cells during MCMV infection. In addition, we will define the rules for antigen recognition of MCMV-infected cells by the γδ TCR. This will, in the long-term, define the ligands of the γδ TCR on virus infected cells. This project is part of the application for a Research Group FOR2799 “Receiving and Translating Signals via the γδ T Cell Receptor” and the project will benefit from the interactions with the other groups within the FOR2799 which are detailed in the application.