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

62 5 Major Histocompatibility Complex Modulation and Loss
Fig. 5.3 The MHC class II APM. MHC class II
molecules present peptides derived from exogenous
antigens internalized into the endocytic
pathway. Briefly, HLA class II heterodimers assemble
in the ER with the Ii to form nonameric
a/b/Ii complexes. These are targeted to the
MHC class II endocytic compartment where the
MHC class II-associated Ii is degraded, leaving
the CLIP peptide within the MHC class II binding
groove. CLIP can be exchanged for antigenic
peptides catalyzed by HLA-DM molecules. The
HLA-DM-dependent peptide loading is controlled
by HLA-DO. The peptide-loaded MHC
class II molecules are then transported to the
cell surface for presentation to CD4 + T lymphocytes.
(see color plates page XX)
docytic pathway, termed MIIC [14]. The MHC class II-associated Ii is proteolytically
degraded in different steps, leaving only a small fragment, the MHC class II-associated
Ii peptide (CLIP), in the MHC class II binding groove. CLIP is then subsequently
exchanged by antigenic peptides. This process is catalyzed by the HLA-DM
molecule, another HLA-like molecule, that facilitates CLIP removal and stabilizes
the peptide-free status of the MHC class II molecules [15]. Thus, HLA-DM acts as a
peptide editor that favors presentation of stably bound peptides, thereby critically affecting
the peptide repertoire presented to the T cells. The MHC class II-encoded heterodimer
HLA-DO consisting of HLA-DOA and -DOB inhibits the HLA-DM-dependent
catalysis of peptide loading, suggesting that HLA-DO also affects the antigenic
peptide repertoire presented by MHC class II molecules to CD4 + T cells [16, 17], in
particular by inhibiting presentation of large-sized peptides [18].