The Major Histocompatibility Complex (MHC) and the proteasome-ubiquitin pathway in T cell development

The essential role of classical MHC molecules in T cell development as well as the proteasome role in antigen processing for MHC-mediated antigen presentation to T cells is well established. However, the contribution of nonclassical MHC molecules, the signals evoked by the MHC-TCR interactions, the signaling role of the proteasome-mediated proteolysis, and the regulation of the proteasome-ubiquitin proteolysis remain to be clarified. Here we address these more subtle but essential aspects of T cell development. We obtained mice deficient for MHC molecules encoded by the H-2K and H-2D genes. KbDb -/- mice have greatly reduced numbers of mature CD8+ T cells, indicating that selection of CD8+ T cells can not be compensated for by [beta]2m-associated molecules other than classical H-2K and D locus products. Spleen cells from KbDb -/- mice generate strong CD8+ MHC class I-specific responses after in vivo priming. Thus, a minor population of CD8+ T cells arises in the complete absence of classical MHC class I molecules. KbDb -/- animals also have self-tolerant natural killer (NK) cells that retain their cytotoxic potential. We utilize a fetal thymic organ culture (FTOC) system with a panel of proteasome inhibitors to implicate the proteasome in thymocyte apoptosis and negative selection. We find that proteasome inhibitors do not completely block but rather delay both dexamethasone- and antigen-triggered thymocyte apoptosis. We also show that proteasome activity is increased in apoptotic thymocytes,

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Vugmeyster, Yulia, 1973-

Advisor dc:contributor.advisor

• Hidde L. Ploegh.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/8322

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/8322