Thymoproteasome: Role in Thymic Selection and Clinical Significance as a Diagnostic Marker for Thymic Epithelial Tumors
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REVIEW
Thymoproteasome: Role in Thymic Selection and Clinical Significance as a Diagnostic Marker for Thymic Epithelial Tumors Utano Tomaru • Masanori Kasahara
Received: 31 October 2012 / Accepted: 26 April 2013 Ó L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013
Abstract The thymoproteasome is a specialized type of proteasomes expressed exclusively in the thymic cortex. It has a unique catalytic subunit b5t with unusual enzymatic activity. The thymoproteasome exhibits lower chymotrypsin-like activity than other forms of proteasomes such as constitutive proteasomes and immunoproteasomes. Its cleavage specificity appears uniquely suited for the production of peptides that mediate positive selection of CD8? T cells. Similar to major histocompatibility complex molecules and T/B-cell receptors, the thymoproteasome occurs only in jawed vertebrates, suggesting that it evolved concomitant with the cardinal elements of adaptive immunity. b5t can be used as a marker in the differential diagnosis of thymic tumors. It is expressed in most type B and some type AB thymomas, but not in type A thymoma, thymic carcinoma, or tumors of non-thymic epithelial origin. Keywords Thymoproteasomes b5t Thymus Positive selection Thymoma Thymic carcinoma Abbreviations cTEC Cortical thymic epithelial cell DC Dendritic cell IFN-c Interferon-c MHC Major histocompatibility complex mTEC Medullary thymic epithelial cell TAP Transporter associated with antigen processing TCR T-cell receptor U. Tomaru (&) M. Kasahara (&) Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan e-mail: [email protected] M. Kasahara e-mail: [email protected]
Introduction The proteasome constitutes the central proteolytic component of the ubiquitin–proteasome system required for the maintenance and regulation of various cellular processes (Coux et al. 1996; Tanaka et al. 2012). In the immune system, proteasomes are responsible for the generation of peptides presented by major histocompatibility complex (MHC) class I molecules (Kloetzel 2001; Rock and Goldberg 1999; Tanaka and Kasahara 1998). To date, three types of proteasomes have been identified in jawed vertebrates; the constitutive or housekeeping proteasome highly conserved from yeast to man; the immunoproteasome, which is induced by stimulation with interferon (IFN)-c in most tissues, but is constitutively expressed in immune tissues such as spleen and thymus (Tanaka and Kasahara 1998); and the thymoproteasome expressed exclusively in the thymic cortex (Murata et al. 2007; Tomaru et al. 2009). Accumulated evidence indicates that the latter two forms of proteasomes play important roles in adaptive immunity. The immunoproteasome efficiently produces antigenic peptides capable of binding to MHC class I molecules, thus facilitating elimination of virus-infected and tumor cells by cytotoxic T cells (Tanaka and Kasahara 1998). On the other hand, the thymoproteasome plays a crucial role in positive selection of CD8? T cells
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