IL4Ra Controls The Medullary Dwell Time Of Mature Thymocytes By Scheduling Their Release From The Thymus

Abstract

Following their generation, newly produced single positive (SP) thymocytes must remain in the thymus to undergo post-selection maturation, a process supported by the thymic medulla. This ensures that SP thymocytes are equipped with functional competence prior to S1PR1-mediated thymic emigration. Despite this importance, the intrathymic mechanisms that control the balance between retention and release of SP thymocytes is unclear. Here, we describe a cell autonomous requirement for IL4Ra-signalling in SP thymocytes, that determines the duration of their medullary occupancy. We show that the period of this occupancy is prolonged in the absence of IL4R expression by SP thymocytes, which occurs as a result of impaired interactions with medullary thymic epithelial cells (mTEC). Importantly, extending the duration of medullary occupancy enhances the maturational status and functional capabilities of SP thymocytes, including improved TNF and IL2 production. Collectively, we show that IL4Ra regulates the medullary occupancy of mature thymocytes, which in turn determines the functional properties of thymic output.