Untersuchung des Einflusses von regulatorischen T Zellen auf die Immunantwort gegen eine Maus-Cytomegalovirus-Infektion
Final Report Abstract
Cytomegaloviruses have evolved numerous strategies to modulate innate and adaptive immune responses to infection, likely contributing to the lifelong persistence of this virus in its host. Dendritic cells (DC) are a target of CMV infection and play a central role in regulating both innate and adaptive immunity. CMV infection of DC results in the downregulation of both MHC and positive costimulatory molecules from the cell surface, while the levels of negative cosignaling ligands, such as Programmed-Death Ligand-1 (PD-L1), remain high. The downregulation of positive costimulatory molecules is achieved by the concerted action of several, specific viral genes. A result of the cooperative downregulation of positive costimulatory molecules, these infected DC severely stunt antigen-specific T cell responses. This has also been observed in mice deficient for B7.1/B7.2 and in both cases, this reduction in T cell function was reversible by blocking PD-L1 interaction. Further addressing the role of B7 costimulation in MCMV infection, mice deficient for both B7 molecules show significantly decreased early MCMV-specific CD8 T-cell. However, the CD8 T-cell responses that peak during latent infection were unaltered in B7.1/B7.2 deficient mice. Using a virus deficient for the genes downregulating B7.1 and B7.2, we demonstrated that this virus has a reduced replication capacity in vivo and elicits greatly reduced CD4 and CD8 T cell responses at late times post infection. Surprisingly, at this point we have no indication that MCMV-infection leads to the induction of regulatory T cells. Instead, we discovered how several immunomodulatory genes work together in the modulation of adaptive T cell responses. These analyses demonstrate that the MCMV genome is fine-tuned for optimal modulation of the host with several viral genes synergistieally contributing to dampen T cell responses. The projects carried out during this fellowship period were collaborative in nature. This provided an access to complex techniques the learning of which would have taken a lot more time had I not been able to learn from "the professionals". Furthermore, the conversations and time spend together was a fun, adventurous learning experience providing a basis of connections available for collaborations in the future, at times when none of us will be working at the LIAI anymore but in leadership positions somewhere else. Being in the supportive work environment at the LIAI with a structure much different from what I have experienced during my PhD time in Germany provides an insight into other possible ways of "doing science". Taken together, the experiences, contacts and skills acquired during those two years provide an excellent basis for a successful scientific career.
Publications
- "Lymphotoxin-mediated crosstalk between B-cells and stroma promotes the initial type I interferon response to cytomegalovirus" Cell, Host and Microbes, 14;3(2):67-76
Schneider K, Loewendorf A, de Trez C, Fulton J, Rhode A, Shumway H, Ha S, Patterson G, Pfeffer K, Nedospasov S A, Ware C and Benedict C
- (2007) OX40 costimulation promotes persistence of cytomegalovirus-specific CD8 T Cells: A CD4-dependent mechanism. J Immunol. 15;179(4):2195-202
Humphreys IR, Loewendorf A, de Trez C, Schneider K, Benedict CA, Munks MW, Ware CF, Croft M
- "Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell response." J Immunol. 2008 May 15;180(10):6472
Arens R, Wang P, Sidney J, Loewendorf A, Sette A, Schoenberger SP, Peters B, Benedict CA
- "Dendritic cell programming by cytomegalovirus stunts naive T cell responses via the PD-L1/PD-1 pathway." J Immunol. 2008 Apr 1;180(7):4836-47
Benedict CA, Loewendorf A, Garcia Z, Blazar BR, Janssen EM
