EBI2 contributes to central tolerance by promoting rapid motility of medullary thymocytes

Abstract

Abstract Maturing thymocytes enter the thymic medulla, where they encounter numerous self-antigens presented by antigen presenting cells (APC). Those thymocytes that are strongly self-reactive undergo either negative selection or diversion into the regulatory T cell lineage. Although the majority of the proteome is expressed in the medulla, many self-antigens are expressed by only a minor fraction of medullary APC; thus, thymocytes must efficiently enter the medulla and scan APC to ensure central tolerance. Chemokine receptors promote lymphocyte migration, organization within tissues, and interactions with APC in lymphoid organs. The chemokine receptor EBI2 governs the localization of T cells, B cells, and dendritic cells (DC) during immune responses in secondary lymphoid organs. However, the role of EBI2 in thymocyte development has not been elucidated. Here, we demonstrate that EBI2 is expressed by murine CD4+ single positive (CD4SP) thymocytes and thymic DC. EBI2 deficiency did not impact thymocyte cellularity or subset distribution, but did alter the TCR repertoire. Furthermore, EBI2 deficiency impaired negative selection of OT-II TCR transgenic thymocytes responding to an endogenous self-antigen. Two-photon imaging revealed that EBI2 deficiency resulted in reduced migration and impaired medullary accumulation of CD4SP thymocytes. These data identify a role for EBI2 in promoting efficient central tolerance.