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Link between Organ-specific Antigen Processing by 20S Proteasomes and CD8⁺ T Cell–mediated Autoimmunity

Ulrike Kuckelkorn¹, Thomas Ruppert¹, Britta Strehl¹, Peter R. Jungblut², Ursula Zimny-Arndt², Stephanie Lamer², Immo Prinz², Ilse Drung¹, Peter-M. Kloetzel¹, Stefan H.E. Kaufmann² and Ulrich Steinhoff²

¹ Institute of Biochemistry, Charite, Humboldt University
² Max-Planck Institute for Infection Biology, D-10117 Berlin, Germany

Address correspondence to U. Steinhoff, Max-Planck Institute for Infection Biology, Schumannstr. 21/22, D-10117 Berlin, Germany. Phone: 49-30-28460-525; Fax: 49-30-28460-503; E-mail: steinhoff{at}mpiib-berlin.mpg.de

Adoptive transfer of cross-reactive HSP60-specific CD8⁺ T cells into immunodeficient mice causes autoimmune intestinal pathology restricted to the small intestine. We wondered whether local immunopathology induced by CD8⁺ T cells can be explained by tissue-specific differences in proteasome-mediated processing of major histocompatibility complex class I T cell epitopes. Our experiments demonstrate that 20S proteasomes of different organs display a characteristic composition of and ß chain subunits and produce distinct peptide fragments with respect to both quality and quantity. Digests of HSP60 polypeptides by 20S proteasomes show most efficient generation of the pathology related CD8⁺ T cell epitope in the small intestine. Further, we demonstrate that the organ-specific potential to produce defined T cell epitopes reflects quantities that are relevant for cytotoxic T lymphocyte recognition. We propose tissue-specific antigen processing by 20S proteasomes as a potential mechanism to control organ-specific immune responses.

Key Words: antigen processing • proteasomes • intestinal mucosa • T cell epitopes • autoimmunity

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