In the last decade, we have gained substantial knowledge on the control of the fate of innate lymphoid cells (ILCs), a group of lymphocytes including lymphoid tissue inducer (LTi) cells and natural killer (NK) cells, which lack, in contrast to T and B cells, somatically rearranged antigen (Ag) receptors. ILCs are characterized by producing cytokines analogous to Th1, Th2 and Th17 cell subsets and hence divide into 3 major families: 1) INFg-producing ILC1, 2) IL-4, -5, and -13-producing ILC2, and 3) IL-22 and -17-producing ILC3; the latter depend on the nuclear orphan receptor RORgt. We and others have recently reported that ILC3s can function as antigen-presenting cells (APCs) for CD4 T cells. The identification of pathways that regulate ILC/T cell interaction is essential for a better understanding of how ILCs link the innate and adaptive immune system and may contribute to protective or pathological immune responses.

Hypotheses. A main focus of this proposal is to discriminate ILC/T cell interaction under steady-state and activating conditions in various organs including lymph node, spleen and gut in vivo. Using genetically modified mouse models we postulate that only fully activated ILCs can elicit CD4T cell responses and that the intestinal cytokine milieu prevents activation of ILCs.

Specific aims. This proposal aims at understanding:

.    Kinetics of cognate ILC3 - T cell interaction in a lymph node.

.    Induction of ILC3 and T cell responses in the spleen vs. intestine.