Charakterisierung der IL-10 Antwort bei der akuten und der chonischen LCMV-Infektion in vivo und in vitro und Etablierung einer effizienten antiviralen Therapie basierend auf der IL-10 Rezeptorblockade
Final Report Abstract
A robust T cell response is the hallmark of an effective immune response to a variety of invading viruses. In many acute infections, the clearance of the viral pathogen is associated with a short and vigorous T cell response followed by development of pathogen-specific immune memory. However, some viruses can establish persistent infection in their respective host, during which an ongoing T cell response is required in order to prevent overwhelming viral replication. Little is known about the factors that sustain the T cell response in the persistent phase of a viral infection. During this funding period, I have studied the role of OX40 during persistent viral infection. OX40 (CD134) is an inducible co-stimulatory receptor that belongs to the TNF receptor superfamily (TNFRSF). It is primarily expressed on activated T cells and interactions with its ligand (OX40L) promote survival but also division and cytokine production of T cells in various settings. Moreover, therapeutic stimulation of the OX40 receptor through an agonistic, monoclonal antibody has been shown to enhance antigen-specific T cell responses in animal models as well as in humans. However, the role of OX40 in the setting of a persistent infection has not been studied previously. (1) These studies have demonstrated that ligation of the OX40 molecule, which is expressed on T cells targeting the virus, is critically required in order to sustain the anti-viral immune response. We could show that virus-specific T cells express high levels of OX40 on their surface during persistent infection and demonstrate that OX40-deficient T cells fail to accumulate sufficiently. Consequently, mice lacking the OX40 receptor are incapable of controlling viral replication. Collectively, these findings establish OX40 as a crucial signaling molecule during a persistent viral infection. (2) Since therapeutic OX40 stimulation has been shown to be a powerful tool to enhance antitumor or vaccine induced immune responses, we investigated whether OX40 stimulation has the potential to prevent establishment of persistent infection. Unexpectedly, we observed that early OX40 stimulation after LCMV infection resulted in a sustained reduction of cellular and humoral antiviral immunity and OX40 treated mice were unable to contain LCMV clone 13 infection. We found that OX40 stimulation promoted the expression of the transcriptional repressor Blimp-1 and a Th1-like effector differentiation of virus-specific CD4 T cells, which potenüy inhibited the emergence ofa follicular T helper cell response. Collectively, our data provide novel insights into how OX40 signaling can profoundly alter T cell differentiation and has important implications for immunotherapeutic applications involving T cell co-stimulation.
Publications
- Protection against or triggering of Type 1 diabetes? Different roles for viral infections. Expert Rev Clin Immunol. 2011 Jan;7(1):45-53
Boettler T, von Herrath M
- Type 1 diabetes vaccine development: animal models vs. humans. Hum Vaccin. 2011 Jan 1;7(1):19-26. Epub 2011 Jan 1
Boettler T, von Herrath M
- Can an immune-regulatory vaccine prevent HIV infection? Expert Rev Anti Infect Ther. 2012 Mar;10(3):299-305
Boettler T,Cunha-Neto E, Kalil J, von Herrath M
- IL-7 receptor α blockade, an off-switch for autoreactive T cells. Proc Natl Acad Sci U S A. 2012 Jul 31:109(31):12270-1. Epub 2012 Jul 23
Boettler T, von Herrath M
- TGF-β Blockade Does Not Improve Control of an Established Persistent Viral Infection. Viral Immunol. 2012 Jun;25(3):232-8. Epub 2012 May 23
Boettler T, Cheng Y, Ehrhardt K, von Herrath M
