ILC2-derived LIF licences progression from tissue-localized to systemic immunity

Migration and homing of immune cells are critical for immune surveillance. Efficient trafficking is mediated by cellular expression of combinations of adhesion and chemokine receptors which guide immune cells, in response to chemokine signals, to specific locations within tissues and the lymphatic system. This supports tissue-localized immune reactions and systemic immunity. However, fundamental questions remain as to how these signals are initiated and regulated. Here we show that disruption of leukaemia inhibitory factor (LIF) production from group 2 innate lymphoid cells (ILC2s) prevents immune cells from leaving the lungs and migrating to the lymph nodes. During pulmonary viral infection this dysregulation leads to plasmacytoid dendritic cells becoming retained in the lungs where they improve tissue-localized anti-viral immunity. By comparison, during chronic allergen challenge the accumulation of immune cells in the lung leads to the pronounced formation of tertiary lymphoid structures in the lung, and a failure to seed the lymph nodes. Mechanistically, ILC2-derived LIF induces the production of the chemokine CCL21 from lymphatic endothelial cells lining the pulmonary lymphatic vessels, thereby licencing the homing of CCR7+ immune cells to lymph nodes. Thus, ILC2-derived LIF production dictates the egress of immune cells from the lungs regulating tissue versus systemic immunity and the balance between allergen and viral responsiveness in the lungs.