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Residency and trafficking of ILC2s in steady state and Th2 induced inflammatory conditions

Abstract : ILC2s are found in mucosal tissues as lung and intestine, in lymph nodes, and in metabolic tissues such as the adipose tissues. They play important role in maintaining or inducing type-2 immune responses as innate equivalent of Th2 lymphocytes. They are activated by alarmins (IL-25 and IL-33) and by external activators (allergens, metabolites and neuromediators). ILC2s are secreting type-2 cytokines to facilitate the activation of other cells and to induce an important repair program. Their activation allows large type of events as diverse as myeloid cells recruitment and activation, mucus production, muscle contractility and tissue repair. They have key role in lung and adipose tissue development and maintain their homeostasis by early responding against parasitic pathogens. Abnormal activation of ILC2s is also participating to chronic diseases.ILCs are mostly considered as resident cells. However, different studies suggested that migration could be important for the maturation of their effector capacities and to correctly target the injured tissue. Circulation and trafficking of ILC subsets is still unclear. No mechanism is yet available to explain the turnover of ILC2s and how they can act in many tissues following stimuli.We found that large numbers of mature and immature ILC2s could be collected in the thoracic duct lymph of mice perfused over several hours, showing that ILC2s are in fact actively circulating through the hemo-lymphatic circuit. Furthermore, circulating mature ILC2s could be separated into three distinct subsets depending on their pattern of receptor and adhesion molecule expression. Cell transfer experiments proved that specific patterns are representative of specific tropism for gut, lung and adipose tissues.To analyse ILC2 behaviour in the context of a type-2 response, we injected IL-25 and IL-33 before lymph collection. IL-33 stimulation largely enhanced the number of circulating ILC2s in the lymph. These different ILC2 tissue targeted subsets responded differently to IL-33. Specifically, gut-trafficking ILC2s were mainly stimulated to proliferate whereas lung and adipose tissue subsets were stimulated to produce IL-13, IL-5 and Areg. This suggests that, in ILC2s, specific tissue targeting is associated with already imprinted functions while transiting through the hemo-lymphatic system. We confirmed these functions of circulating ILC2 subsets in more physiological context by mimicking allergy and helminth infection (stimulation by papain and succinate) where specific migration to lungs and intestine play important roles in mounting the type-2 response by IL-5/IL-13 secretion, and also initiating tissue repair by Areg production. Interestingly, we showed that lung migrating ILC2s participated to resident pool renewal that main function is Areg production. Finally, we characterized important trafficking of ILC2 at different stages of Nippostrongulus brasiliensis infection, confirming the functional relevance of ILC2 trafficking.
Keywords : ILC2 circulation
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Maxime Petit. Residency and trafficking of ILC2s in steady state and Th2 induced inflammatory conditions. Human health and pathology. Université de Paris, 2019. English. ⟨NNT : 2019UNIP7095⟩. ⟨tel-03131661⟩

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