title: CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance.
abstract: Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Zicheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Lancaster
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712.
authors.forename: Chayanit
authors.initials: C
authors.lastname: Sasiponganan
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712 lehrlich@austin.utexas.edu.
authors.forename: Lauren I R
authors.initials: LI
authors.lastname: Ehrlich
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology; D002450:Cell Communication; D061167:Central Tolerance; D002633:Chemotaxis; D003713:Dendritic Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054398:Receptors, CCR4 / Q000502:physiology*; D054400:Receptors, CCR7 / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D060168:Thymocytes / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D001324:Autoantigens; C515355:Ccr4 protein, mouse; C515371:Ccr7 protein, mouse; D054398:Receptors, CCR4; D054400:Receptors, CCR7