Regulation of effector and memory T cell responses in peripheral tissues

• Applicant: Dr. Katharina Hochheiser
• Subject Area: Immunology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 263778188

The immune system is required for the protection of the organism against microbial infections and neoplastic cells. However, if it turns against endogenous or innocuous antigens, it can also cause great harm. T cells play a central role in both protective as well as deleterious immune responses. The regulation of effector T cell responses and APC-T cell interactions in peripheral tissues remain poorly characterized, mainly due to the lack of appropriate tools and methods to visualize cell functionality in vivo. Previous work in the laboratory of Dr. Gebhardt overcoming these obstacles has revealed differential requirements for the re-stimulation of CD4+ and CD8+ effector T cells in the herpes simplex virus 1 (HSV-1) infected skin. IFNg+ CD4+ effector T cells can be found in all areas of the skin and are re-stimulated by professional APCs presenting exogenously acquired viral antigen. In contrast, CD8+ effector T cells can exclusively be re-stimulated by directly infected cells. Cross-presenting DCs able to stimulate naïve CD8 T cells fail to induce IFNg production and IFNg+ CD8 T cells are thus only found in the infected epidermis.The aim of this project is to understand the molecular mechanisms behind the differential requirements and conditions for reactivation of CD4+ and CD8+ effector T cells, especially the importance of direct infection for CD8+ effector T cell activation. Using techniques such as qPCR, Western Blot, and flow cytometry the equipment of infected and non-infected APCs will be compared quantitatively at the transcriptional and translational level with respect to various stimulatory and inhibitory molecules. Different T cell effector functions such as production of pro-inflammatory and regulatory cytokines as well as cytotoxicity will be analysed by flow cytometry and immunofluorescence microscopy in a variety of infectious disease and autoimmunity models in the skin and vaginal mucosa to distinguish general mechanisms and disease-specific characteristics. Additionally, it will be investigated whether similar mechanisms also operate in the re-activation of memory T cells in protective recall responses. Finally, interactions between different memory T cell subsets and their contributions to protective immunity shall be investigated.The results of this project will reveal how peripheral T cell functions are regulated in protective as well as pathological immune responses. As a consequence, they might lead to the identification of novel therapeutic and prophylactic targets for treatment of infection and autoimmunity.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Dr. Thomas Gebhardt