CCR7-mediated migration of developing thymocytes to the medulla is essential for negative selection to tissue-restricted antigens

Abstract

Immature double-positive thymocytes are generated in the thymic cortex, and on positive selection, are induced to differentiate into mature single-positive thymocytes and relocate to the medulla. CCR7 is pivotal for cortex-to-medulla migration of positively selected thymocytes, and CCR7-mediated migration to the medulla is essential for establishing central tolerance, thereby, preventing tissue-specific autoimmunity. However, it was unclear how CCR7-mediated migration to the medulla affects the establishment of self-tolerance. Here, we show that the deletion of thymocytes specific for insulin-promoter-driven tissue-restricted antigens (TRAs) is significantly impaired in CCR7-or CCR7-ligand-deficient mice. These results indicate that CCR7-mediated migration to the medulla contributes to the negative selection of TRA-reactive thymocytes.chemokine ͉ self-tolerance ͉ thymic medulla ͉ thymic epithelial cell T he repertoire of T cells is formed primarily in the thymus. Thymic microenvironments, consisting of various thymic stromal cells, sequentially support the development and selection of thymocytes. In the cortex, cortical thymic epithelial cells (cTECs) present a set of self-peptides, because cTECs express unique proteasomes containing ␤5t (1) and lysosomal proteases (2, 3), and are autophagous (4). Immature CD4 ϩ CD8 ϩ [double positive (DP)] thymocytes that express the virgin repertoire of the T cell receptors (TCRs) are generated in the cortex and selected via interaction between the TCRs and the self-peptide/ MHC complexes expressed by cortical cells, including cTECs and hematopoietic cells (5). DP thymocytes that receive TCRmediated positive-selection signals survive, differentiate into[CD8 single positive (CD8SP)] thymocytes, and relocate to the medulla, where they further interact with the self-peptides displayed in the medullary microenvironments. Medullary thymic ECs (mTECs) express a diverse set of tissue-restricted antigens (TRAs), such as insulin and salivary proteins, which are regulated in part by the nuclear factor Aire (6, 7) and contribute to the deletion of TRA-reactive semimature SP thymocytes (8,9). Thymocytes that are reactive to TRAs are also deleted by their interaction with bone marrow-derived antigen-presenting cells, such as dendritic cells (10). Thus, the stepwise localization of developing thymocytes, initially in the cortex and subsequently in the medulla, appears pivotal in the generation of a diverse, yet self-tolerant, repertoire of T cells. Several chemokines in the thymus have roles in positioning the developing thymocytes (11). Among these chemokines, the CCR7 ligands (CCR7L: CCL19 and CCL21) regulate the migration of positively selected thymocytes from the cortex to the medulla. When they receive positive-selection-inducing TCR signals, cortical DP thymocytes increase their expression of CCR7 on the cell surface, whereas CCR7L in the thymus is predominantly produced by mTECs and distributed in the medulla (12). Thymocytes generated in the absence of CCR7 or CCR7L are defective in...

Three-Dimensional Visualization of the Mouse Thymus Organization in Health and Immunodeficiency

“…2D illustrates a representative WT thymic section exhibiting a welldefined CMJ. In agreement with previous studies (11,22,23), medullary regions varied considerably in size and shape. To better apprehend this complexity, we reconstructed thymic lobes by FOR3D ( Fig.…”

CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity

“…[9][10][11][12][13] These receptors are expressed on developing thymocytes at various stages of their maturation in the thymus and thymocytes are guided by CCX-CKR-ligand chemokines expressed by thymic epithelial cells (TECs) to distinct niches for optimal thymocyte differentiation and selection to proceed. 9 Deletion of CCR7 impairs normal thymocyte development [14][15][16][17][18][19][20][21] and leads to impaired negative selection that result in spontaneous autoimmunity. 16,22,23 Specifically, CCR7 promotes seeding of the thymus by BM-derived progenitors, 15,21 directs outward migration of double negative (DN) thymocyte precursors from the medulla to cortex, 18 and directs inward migration of positively selected, single positive (SP) thymocytes from the cortex to medulla.…”

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

“…GIT2 − / − DP cells are hyper-responsive to chemotactic cues, which bias localization in the cortex, leading to perturbations in the positive selection process 12 . CCR7-deficient mice develop autoimmunity because of defective negative selection [13][14][15][16] . However, the mechanisms by which thymocyte trafficking controls these selection processes are not well understood.…”