Adaptive Immune Regulation

Tumor-antigen specific CD4 T cell proliferation in a tumor draining lymph node in the absence or presence of Treg cells.

The powerful armada of immune cells can eliminate numerous of invading pathogens, yet turn a blind eye to self-tissue. The thymus contributes during T cell differentiation by depleting self-reactive T cell clones. This central deletion is powerful, yet imperfect. Self-reactive T cells enter the periphery, and are responsible for many autoimmune diseases.

The immune system has evolved a second layer of peripheral tolerance mechanism to keep these “forbidden clones” as well as excessive or unwanted immune reactions under control. These regulatory mechanisms are of particular interest, since they impinge on many diseases or treatment strategies, including autoimmunity, anti-tumor-immunity, transplantation, and persistent infections. Especially, anti-tumor-immunity is strongly compromised by peripheral tolerance.
A specialized subset of CD4+ T cells, commonly termed regulatory T(reg) cells, are key players. They are characterized by the expression of the forkhead/winged helix transcription factor Foxp3.

This project will characterize molecular mechanisms involved in Treg cell biology. There is limited knowledge on how these specialized cells influence other adopotive or innate immune cells as well as non-immune cells. Different experimental systems are in place to test for function including relevant in vivo model systems such as autoimmune diabetes and spontaneous tumors

Innate Immune Regulation

A and B) Developmental relationship between monocytes and dendritic cells (DCs); C) Blood monocyte subsets (Ly6C-high and Ly6C-low)

The mononuclear phagocyte system (MPS), comprising monocytes, macrophage and dendritic cells (DCs), is involved in tissue homeostasis as well as various pathological conditions like pathogen defense, wound healing and cancer. Monocytes and macrophages are getting increasing attention in the last few years and research is focusing on origin and function of these cells. Studies revealed that monocytes/macrophages and DCs share a common lineage. We could recently identify a novel progenitor restricted to both monocyte subsets and monocyte-derived macrophages (Figure A and B). We termed this population cMoP (for common monocyte progenitor). Our study filled a critical gap in the current understanding of monocyte development.

The recruitment of subpopulations of monocytes (Figure C) or macrophages derived thereafter can heavily influence the local inflammatory state in a giving tissue. Subsets of monocytes were associated with phagocytic and inflammatory functions whereas allied subsets had attenuated inflammatory properties, can dampen inflammation and could promote wound healing and tissue repair. Very strong differences in function have been reported whether the primary inflammatory stimulus was a bacterial infection or a growing tumor. Especially, tumor-associated macrophages (TAM) are believed to be involved and promote tumor initiation, progression and metastasis. Yet, still little is known about their function, plasticity and the interactions with other immune cells. How do they help to establish or break immune tolerance? The aim of this project is to understand the development, functions and disease mechanisms of these innate players.

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