Thymic microenvironments for T-cell repertoire formation.
Functionally competent immune system includes a functionally competent T-cell repertoire that is reactive to foreign antigens but is tolerant to self-antigens. The repertoire of T cells is primarily formed in the thymus through positive and negative selection of developing thymocytes. Immature thymocytes that undergo V(D)J recombination of T-cell antigen receptor (TCR) genes and that express the virgin repertoire of TCRs are generated in thymic cortex. The recent discovery of thymoproteasomes, a molecular complex specifically expressed in cortical thymic epithelial cells (cTEC), has revealed a unique role of cTEC in cuing the further development of immature thymocytes in thymic cortex, possibly by displaying unique self-peptides that induce positive selection. Cortical thymocytes that receive TCR-mediated positive selection signals are destined to survive for further differentiation and are induced to express CCR7, a chemokine receptor. Being attracted to CCR7 ligands expressed by medullary thymic epithelial cells (mTEC), CCR7-expressing positively selected thymocytes relocate to thymic medulla. The medullary microenvironment displays another set of unique self-peptides for trimming positively selected T-cell repertoire to establish self-tolerance, via promiscuous expression of tissue-specific antigens by mTEC and efficient antigen presentation by dendritic cells. Recent results demonstrate that tumor necrosis factor (TNF) superfamily ligands, including receptor activating NF-kappaB ligand (RANKL), CD40L, and lymphotoxin, are produced by positively selected thymocytes and pivotally regulate mTEC development and thymic medulla formation.
Nitta
Takeshi
T
Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
Murata
Shigeo
S
Ueno
Tomoo
T
Tanaka
Keiji
K
Takahama
Yousuke
Y
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D054400:Receptors, CCR7 / Q000276:immunology* / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism
D011948:Receptors, Antigen, T-Cell; D054400:Receptors, CCR7