Kallies- Ludwig-Portugall collaborative projects

The adipose harbors large numbers of diverse hematopoietic cells that control adipose tissue health and organismal metabolism. Regulatory T cells (Tregs) and type 2 innate lymphocytes (ILC2) play central roles in this cellular network by limiting adipose tissue inflammation. We and others have shown, that adipose tissue-resident Tregs and ILC2 express a unique set of surface molecules, including the IL-33 receptor, which was required for their development. Administration of IL-33 resulted in adipose tissue-specific population expansion of Tregs and ILC2 and improved metabolic parameters in obese mice. T cell receptor induced transcription factors IRF4 and BATF were essential for Tregs to adopt the IL-33 responsive state. We have now uncovered an additional layer of complexity in the molecular network controlling adipose tissue health. Hormones contributed to Treg and ILC2 differentiation and maintenance in a gender and adipose tissue-specific manner. This resulted in stark differences in the composition and function of the adipose in male and female mice that were at least in part Treg and ILC2 intrinsic. Using novel mouse models and molecular techniques we are currently unraveling the cellular and molecular components of the lymphocyte network that controls adipose tissue homeostasis and maintains healthy organismal metabolism.

Immune suppression is important during homeostasis and inflammation to prevent organ damage. Foxp3+ regulatory T cells (Tregs) and other suppressive cells, e.g. myeloid de- rived suppressor cells (MDSCs), are critical for limiting damage during inflammation. Kallieshas demonstrated that thymus-derived (t) Tregs undergo further differentiation and specialization in the periphery, giving rise to specialized Tregs that produce IL-10 and home to non-lymphoid tis- sues. Recently, his lab showed that interleukin (IL)-33 and the transcriptional regulators IRF4 and BATF are important for the development of Tregs in the visceral adipose tissue (VAT), and preliminary data suggested that this molecular pathway is also required for other tissue-Tregs, in particular under inflammatory. Recent work by Ludwig-Portugall has shown that antigen-specific Tregs suppress auto-reactive B cells against tissue-specific antigen via PD-1/PD-L1. Further studies revealed that MDSCs suppress kidney inflammation. The present project combines her expertise on immunosuppression with that of Kallieson transcriptional control of lymphocyte differentiation, to examine the regulation of immune suppression in non-lymphoid tissues. We will focus on how tissue-derived cytokines such as IL-33 and transcription factors such as IRF4 and BATF regulate development and function of suppressive myeloid cells including DCs and MDSCs. We will examine the transcriptional and metabolic profile of DCs and MDSCs within inflamed tissue. We will study the impact of myeloid cells on differentiation, population expansion and function of tissue-specific Tregs. We will analyse the role of IL-33, IRF4 and BATF for the differentiation of tissue-specific Tregs in non-lymphoid organs such as skin, kidney or lung and define their molecular and developmental requirements. Finally, we will compare the influence of these regulators on thymus-derived tTregs on that on de novo peripherally induced Tregs (pTreg) to identify differences and commonalities in transcriptional, developmental and metabolic requirements.