Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

30 Cancer Immune Therapie: Current and Future Strategies
Edited by G. Stuhler and P. Walden
Copyright # 2002 Wiley-VCH Verlag GmbH & Co. KGaA
ISBNs: 3-527-30441-X (Hardback); 3-527-60079-5
(Electronic)
3
Processing and Presentation of Tumor-associated Antigens
Peter-M. Kloetzel and Alice Sijts
3.1
The Major Histocompatibility Complex (MHC) Class I Antigen-Processing Pathway
As part of the vertebrate immune surveillance system cytotoxic T cells recognize antigens
which are bound by MHC class I proteins. To allow binding to MHC class I molecules
a protein has to be proteolytically processed to peptides. The recognition of
the MHC±peptide complex on the plasma membrane by a T cell receptor (TCR)
which is specific for a given antigenic peptide bound to a specific MHC class I molecule
eventually leads to T cell activation [1].
Considering the complexity of the MHC class I sequence motifs, any proteolytic system
involved in the generation of immuno-dominant MHC class I epitopes has to be
able to produce peptides of the appropriate size (8±10 residues) and amino acid sequence
diversity, and it has to be able to generate peptides with defined C-terminal
anchor residues in sufficient efficiency from a large variety of different proteins in
the cytosol and nucleus. Today it is widely accepted that the proteasome system is responsible
for the generation of the majority MHC class I ligands [2±4].
The proteasome is the major cytosolic protease complex in eukaryotic cells. It is composed
of a proteolytically active core, i.e. the 20S proteasome and two 19S regulator
complexes which attach to both sides of the barrel-shaped 20S proteasome. The complex
formed by the cylinder-shaped 20S proteasome and the two regulators is called
the 26S proteasome. The 20S proteasome consists of 14 non-identical subunits ranging
in molecular weight from 31 to 21 kDa and is composed of four stacked rings of
seven subunits each. The seven different a subunits form the two outer rings, while
the two inner rings are formed by the seven different b subunits [3]. The proteolytically
active sites are restricted to the lumen of the cylinder and are formed by three of
the seven b subunits, i. e. subunits d (b1), Z (b2) and MB1 (b5). In total, the 20S proteasome
therefore possesses six active sites within the two inner b rings [5, 6].
Proteasome function can be modulated through the interaction with several regulatory
proteins and in order to enter the catalytic chamber protein substrates have to be
in an unfolded or extended conformation [7, 8]. Unfolding of substrates is thought to
be performed by the six ATPases of the 19S regulator complex which directly attach
to the 20S proteasome and form the so-called base structure of the 19S regulator.