In vivo dissection of Foxp3+ regulatory T cell subpopulations and their dependence on TGFß-Smad signaling

• Applicant: Professorin Dr. Susan Mariola Schlenner
• Subject Area: Immunology
• Term: from 2009 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 108974546

A key feature of the immune system is self-tolerance, i.e. the body own’s antigens are distinguished from foreign antigens. Auto-reactive T cells (TC) are negatively selected in the thymus (central tolerance) but some escape negative selection and need to be suppressed in the periphery (peripheral tolerance). A central role in peripheral tolerance do play regulatory TC (Treg). Development, maintenance and function of Treg is strictly dependent on the expression of Foxp3, a forkhead/winged helix-family transcription factor. Lack of Foxp3 and, hence, lack of Treg results in severe autoimmune and inflammatory diseases in humans (IPEX) and mice (scurfy) due to breakdown of self-tolerance. Foxp3+ Treg develop in the thymus (natural Treg) but can also derive from naïve TC in the periphery (induced Treg). The two populations have a similar surface phenotype and, hence, questions on functional differences can not easily be addressed in a minimalmanipulative system. I, therefore, aim to generate mouse strains that possess either natural but not peripheral Treg or vice versa. A side-by-side analysis of such mice will answer questions on the contribution of both populations to the peripheral Treg pool as well as possible functional diversity. The pleiotropic cytokine TGFβ contributes in vitro to conversion of naïve TC into Treg and their maintenance. Mice that possess exclusively natural or induced Treg will be used to clarify to which extent the Smad-dependent TGFβ signaling pathway contributes to maintenance of natural Treg and/or conversion of naïve TC in the periphery. To this end, a Smad-binding site located in the enhancer region of the foxp3 locus will be replaced by a mutated binding site. The roles of Treg subpopulations in a variety of diseases, and factors that influence their generation, survival and function are of high interest not only for basic research but also for future clinical applications.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Harald von Boehmer