Aire regulates medullary epithelial cell production of XCL1, a chemoattractant for XCR1-expressing thymic DCs whose presence in the medulla contributes to the generation of T reg cells.

How self-peptides displayed in the thymus contribute to the development of immunocompetent and self-protective T cells is largely unknown. In contrast, the role of thymic self-peptides in eliminating self-reactive T cells and thereby preventing autoimmunity is well established. A type of proteasome, termed thymoproteasome, is specifically expressed by thymic cortical epithelial cells (cTECs) and is required for the generation of optimal cellularity of CD8+ T cells. Here, we show that cTECs displayed thymoproteasome-specific peptide-MHC class I complexes essential for the positive selection of major and diverse repertoire of MHC class I-restricted T cells. CD8+ T cells generated in the absence of thymoproteasomes displayed a markedly altered T cell receptor repertoire that was defective in both allogeneic and antiviral responses. These results demonstrate that thymoproteasome-dependent self-peptide production is required for the development of an immunocompetent repertoire of CD8+ T cells.

JapanProteasomes are responsible for generating peptides presented by class I MHC molecules of the immune system. b5t, a recently identified proteasome component, is specifically expressed in thymic cortical epithelial cells (cTECs) and plays a pivotal role in generating an immunocompetent repertoire of class I MHC-restricted CD8 1 T cells. Here, we report that b5t is detectable in the thymus as early as E12.5 mouse embryos. We also found that b5t expression in cTECs was detectable in mice deficient for RelB or Rag2, indicating that b5t in cTECs is expressed in the absence of thymic medulla formation or thymocyte development beyond the CD4 À CD8 À stage. b5t expression in the embryonic thymus was not detectable in Foxn1-deficient nude mice, although its expression was not reduced in mice deficient for both CCR7 and CCR9, in which fetal thymus colonization by leukocytes is defective. These results indicate that b5t expression in cTECs is dependent on Foxn1 but independent of thymocyte crosstalk or thymic medulla formation.Keywords: b5t Á Thymic cortex Á Thymic cortical epithelial cell Á Thymoproteasome Supporting Information available online IntroductionProteasomes are multicatalytic protease complexes that are responsible for the regulation of proteolysis in eukaryotic cells and for the generation of antigenic peptides presented by class I MHC molecules [1]. The 20S proteasome is responsible for the proteolytic activity of the proteasome and is composed of 28 subunits (two a-rings with a1-a7 subunits and two b-rings with b1-b7 subunits). Among the subunits, b1, b2, and b5 are responsible for the proteolytic activity [2]. Interferon-g induces the production of a new set of catalytic subunits, b1i, b2i, and b5i, to replace their constitutive counterparts, b1, b2, and b5, thereby forming immunoproteasomes, which are proteasome complexes that possess altered proteolytic activity and participate in efficient antigen presentation and immune response [3]. We have recently identified a novel subunit of the 20S proteasome, b5t, which is specifically expressed in thymic cortical epithelial cells (cTECs) and plays a pivotal role in the development of CD8 1278T cells [4]. In cTECs, b5t, instead of b5 or b5i, is incorporated into the 20S proteasome together with b1i and b2i, thereby forming unique proteasome complexes termed thymoproteasomes [4]. We have reported evidence supporting the concept that cTECs display a thymoproteasome-specific spectrum of class I MHC-associated self-peptides that are required for the development of an immunocompetent repertoire of CD8 1 T cells [5].Thus, b5t expressed by cTECs is indispensable for the development of the self-protective adaptive immune system [6]. The notion that b5t is specifically expressed in cTECs is based on the following findings: (i) the expression of b5t in various adult mouse organs was specifically detected in the thymus by RNA blot analysis and immunoblot analysis [4]; (ii) b5t in adult mouse thymus was specifically detected in Ly51 1 cells in the immunohistological a...

No abstract