NKG2D Receptor-Associated Negative T Cell Modulation in Tumor Immunity

• Applicant: Dr. Henning Mann
• Subject Area: Immunology
• Term: from 2006 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35183097

NKG2D is an activating immunoreceptor that triggers natural killer (NK) cells and costimulates antigen-specific CD8 T cells upon engagement of ligands that are inducibly expressed under conditions of cellular or genotoxic stress (1-3). In humans, these ligands include the major histocompatibility complex (MHC) class I homologes MICA and MICB, which are frequently associated with epithelial tumors (3). MIC ligands may effectively stimulate anti-tumor immune responses at early stages of tumor growth; however, prolonged expression and shedding of these proteins by progressing tumors likely promotes tumor immune evasion by mechanisms that involve NKG2D downmodulation and immunosuppressive T cell expansions (4, 5). Moreover, preliminary observations indicate that sustained NKG2D stimulation on T cells results in substantial reductions of various activation markers (CD25, CD27, CD69, CD86, CCR7 and LAG-3) and signaling proteins (DAP10, DAP12 and CD3ζ), possibly as a result of transcriptional changes and/or targeted degradation. The here proposed research is aimed at exploring the cellular functions that negatively regulate the expression of NKG2D and the diverse activation and signaling proteins. The results will advance knowledge of how progressing tumors negatively modulate the immune system and may be beneficial for cancer immunotherapy approaches.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Thomas Spies