The role of Cbl-b for NK cell function

• Applicant: Professor Dr. Dominik Wolf
• Subject Area: Hematology, Oncology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 220633472

Regulatory T cells, TGF-ß and immune evasion of malignant tumors Recent evidence has demonstrated that regulatory Treg-mediated immunosuppression is among the most important tumour immune-evasion mechanisms and might represent a main obstacle for successful cancer immunotherapy. Treg are characterized by co-expression of CD4, CD25 and the Forkhead Box transcription factor 3 (FoxP3). FoxP3 plays a key role in CD4+CD25+ regulatory T cell function and represents a relatively specific marker for these cells. Treg represent approximately 3-5% of total CD4+ T cells and physiologically act as crucial repressors of autoimmune disorders and transplant rejection. We and others have previously demonstrated that patients suffering from epithelial tumors have an expanded Treg pool in the peripheral blood as well as in the tumor microenvironment. In some tumors, the amount of Treg infiltration to the tumor site even predicts worse clinical outcome, supporting the idea that they play an important role in suppressing an effective tumor immune surveillance. Recruitment of Treg to the tumor microenvironment is primarily mediated via CCL22 and assumed to contribute to local immune-suppression by limiting the anti-tumor immune response within the tumor. The latter comprise not only various T cell subpopulations but also NK1.1-expressing cells types, including classical Natural Killer (NK) cells, NK T cells and NKDC. This idea that Treg execute inhibitory cues on NK cells is supported by our initial observation that isolated Treg are capable of limiting the cytotoxic activity of human NK cells against classical NK target cells. This data was subsequently corroborated in murine models by showing that the underlying mechanism of Treg-induced inhibition of NK reactivity is a marked repression of NKG2D expression. Although the exact mechanism inducing target cell inhibition remains elusive so far, TGF-ß appears to be among the most important factors mediating Treg-induced target cell inhibition. Thus, it is conceivable that the modulation of critical factors regulating TGF-ß sensitivity in effector immune cells (including NK cells) might be a promising approach to limit the inhibitory effects induced by soluble and/or TGF-ß bound to the membrane of Treg.

• DFG Programme: Research Grants
• International Connection: Austria