Adaptive-innate lymphocyte crosstalk - mechanisms, functions and consequences

• Applicant: Professor Dr. Georg Gasteiger
• Subject Area: Immunology
• Term: from 2014 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259808978

Innate lymphocytes, including natural killer cells (NK) and recently discovered novel subsets of innate lymphoid cells (ILC) exert key functions in coordinating local immune responses, including the killing of infected cells, the production of hallmark cytokines that orchestrate immune responses, and the secretion of tissue-protective factors. Innate lymphocytes respond rapidly to environmental cues without the need for further differentiation. The ease of activation needs to be balanced by stringent control mechanisms because excessive activation of innate lymphocytes contributes to a loss of tissue function and facilitates inflammatory processes as well as the exacerbation of infection-associated pathologies. The cellular interactions and the molecular mechanisms governing the regulation and activation of innate lymphocytes are therefore highly relevant for a broad range of physiologic and pathologic immune responses. Current research has largely focused on the role of innate cytokines and alarmins for the homeostasis and function of innate lymphocytes. In addition to their innate effector functions, ILC and NK cells have been found to participate in shaping and regulating adaptive immune responses. Whether the adaptive immune system may in turn contribute to the control of innate lymphocyte function and homeostasis is largely unknown. During my recent work, I have identified novel regulatory interactions between cells of the adaptive immune system and innate lymphocytes mediated by the adaptive cytokine IL-2. We will now determine the signaling pathways involved in the IL-2-dependent tuning of innate effector function. We will establish clinically relevant disease models of respiratory viral infections and asthma to investigate how adaptive T cells sensitized to viral or environmental antigens shape the responses of ILC. We will determine the role of IL-2 for the activation and homeostasis of ILC, screen for novel and for context-dependent functions of ILC, and test the therapeutic implications. In addition, we will study the lineage-relationship and functions of an ILC-like IL-2-dependent subset of NK cells, which expands during chronic infection, inflammation and in tumors. The results from these projects will be tested for their therapeutic relevance, and their significance for human immunobiology. The proposed research agenda is based on sound preliminary data and is organized into three independent projects that each have immediate and long-term aims and share the common objective to identify the molecular and cellular mechanisms of adaptive-innate lymphocyte crosstalk, and to reveal the context-dependent physiological and pathological consequences of the adaptive control of innate lymphocyte function and homeostasis. This will help to improve the therapy and to reduce the morbidity of infections and inflammatory diseases.

• DFG Programme: Independent Junior Research Groups