Human innate lymphoid cells From helper to killer

Innate Lymphoid Cells (ILCs) control tissue and metabolic homeostasis, but also provide protection from infectious diseases. Strategically located in barrier tissues, ILCs produce effector cytokines in an antigen-independent manner, thereby mounting an appropriate immune response to pathogens at mucosal sites. ILCs are classified into three subsets of helper ILCs, each producing their signature cytokines, and cytotoxic Natural Killer (NK) cells. Their plastic nature allows helper ILC subsets to promptly respond to the changing environment by adapting its function and phenotype. However, when not properly regulated, ILCs can contribute to chronic inflammation, autoimmune disease and cancer. Therefore, it is of importance to identify the essential factors involved in the development and functions of ILCs. In this thesis we describe the methods to isolate ILCs from human mucosal tissues. We identified an essential transcription factor for the development of ILCs by studying the immune cell composition of GATA2-deficient patients. Furthermore, we investigated the full spectrum and the plasticity of human ILCs and NK cells in the tonsil and intestine. Thereby we identified cytotoxic ILCs which are distinct from NK cells and unraveled their developmental requirements. Furthermore, we investigated the ILC composition in the inflamed intestinal tissue of Crohn’s disease patients compared to non-inflamed controls, and observed that particular ILC subsets that express high levels of cytotoxic molecules and type 1 cytokines expanded in inflamed tissues. Our findings contribute to a better understanding of the functions of ILCs and their possible roles in inflammatory diseases of the intestine.