Research

Molecular and Cellular Immunology/Focus Immune Regulation – Karsten Kretschmer

In a healthy organism, regulatory T (Treg) cells expressing the transcription factor Foxp3 suppress fatal immune responses against self, thereby preventing catastrophic autoimmunity. Understanding the biology of Foxp3⁺ Treg cells will help to harness their potent suppressor function against unwanted immune responses underlying autoimmune diseases or the destruction of transplanted hematopoietic stem cells.

Previous and Current Research

In mice and men, CD4⁺Foxp3⁺ Treg cells play an essential role in maintaining immune homeostasis throughout life by regulating protective inflammatory responses to pathogens and preventing fatal autoimmunity, such as the autoimmune-mediated destruction of insulin-producing beta cells in type 1 diabetes (T1D). A particularly striking example for the continuous requirement of Foxp3⁺ Treg cell-mediated suppression is the manifestation of aggressive beta cell autoimmunity in a preclinical mouse model for T1D, immediately after experimental Foxp3⁺ Treg cell ablation in initially non-diabetic adults. Conversely, the enhancement of Treg cell-mediated suppression (e.g., by increasing their numbers or activation status in vivo) holds the promise of reinstating immune homeostasis in clinical settings of dysregulated immune responses, including T1D and other autoimmune diseases. Besides the regulation of both innate and adaptive immune responses, other non-immune functions of Foxp3⁺ Treg cells are also emerging, such as the regulation of adipose tissue metabolism, bone-resorbing osteoclasts, or regeneration of injured tissues. Gaining an in-depth understanding of the molecular and cellular mechanisms that govern the biology of Foxp3⁺ Treg cells (including development, lifestyle, and function) offers novel opportunities for the rational design of Foxp3⁺ Treg cell-based therapies.

FUTURE PROJECTS AND GOALS

• Identify molecular pathways that govern the biology of Foxp3⁺ Treg cells, including cell signaling, gene transcription, and epigenetic regulation.
• Dissect Foxp3⁺ Treg cell heterogeneity, with an emphasis on immune and non-immune functions of developmental sublineages.
• Establish approaches to enhance Foxp3⁺ Treg cell activity for promoting antigen-specific immune tolerance in autoimmune diseases.