EBI2 contributes to the induction of thymic central tolerance in mice by promoting rapid motility of medullary thymocytes

• Published in: European journal of immunology 2017-11, Vol.47 (11), p.1906-1917
• Main Authors: Ki, Sanghee, Thyagarajan, Hiran M., Hu, Zicheng, Lancaster, Jessica N., Ehrlich, Lauren I.R.
• Format: Article
• Language: English
• Subjects: 2‐photon; Animal tissues; Animals; Antigen-presenting cells; Antigens; Autoantigens; CD4 antigen; Cell Differentiation - immunology; Cell lineage; Central tolerance; Central Tolerance - immunology; Chemokine receptors; Chemokines; Chemotaxis, Leukocyte - immunology; Clonal selection; Dendritic cells; EBI2; Immune response; Immunological tolerance; Leukocyte migration; Localization; Lymphocytes; Lymphocytes B; Lymphocytes T; Medulla oblongata; Mice; Negative selection; Organs; Proteomes; Receptors, G-Protein-Coupled - immunology; T cell receptors; Thymocyte motility; Thymocytes; Thymocytes - immunology; Thymus; Thymus Gland - immunology; Treg cell differentiation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201747020

Maturing thymocytes enter the thymic medulla, where they encounter numerous self‐antigens presented by antigen presenting cells (APCs). 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 APCs; thus, thymocytes must efficiently enter the medulla and scan APCs to ensure central tolerance. Chemokine receptors promote lymphocyte migration, organization within tissues, and interactions with APCs in lymphoid organs. The chemokine receptor EBI2 governs localization of T cells, B cells, and dendritic cells (DCs) 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 DCs. EBI2 deficiency alters the TCR repertoire, but does not grossly impact thymocyte cellularity or subset distribution. EBI2 deficiency also impairs negative selection of OT‐II TCR transgenic thymocytes responding to an endogenous self‐antigen. Two‐photon imaging revealed that EBI2 deficiency results in reduced migration and impaired medullary accumulation of CD4SP thymocytes. These data identify a role for EBI2 in promoting efficient thymic central tolerance. Developing T cells must enter the thymic medulla and scan numerous antigen presenting cells to encounter the full range of self‐antigens required to induce central tolerance. EBI2, a chemokine receptor expressed by immature medullary thymocytes, promotes thymocyte medullary accumulation and rapid motility, thus contributing to the induction of central tolerance.