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

60 5 Major Histocompatibility Complex Modulation and Loss
MHC class Iantigens, also termed class Ia, are the human leukocyte antigens
(HLA)-A, -B and -C, which play an important role in the antiviral and antitumoral
immunity, and are mostly expressed on nucleus-containing cell types. They consist
of a highly polymorphic heavy chain (HC) which non-covalently associates with the
antigenic peptide and a non-polymorphic light chain, b2-microglobulin (b2-m), and
are characterized by their widespread expression on most tissues, except sperm and
brain.
The MHC also encodes a second set of MHC class Imolecules, the non-classical or
MHC class Ib molecules, which share no homology with the classical MHC class I
antigens. These consist of HLA-E, -F and -G, exhibit a limited polymorphism, and
demonstrate low levels of tissue expression [2].
In addition to the MHC class Ia and Ib antigens, there exist highly polymorphic
MHC class II molecules which are a/b heterodimers encoded by three MHC class II
isotypes, HLA-DR, -DP and -DQ [3]. The normal expression pattern of MHC class II
molecules is restricted to professional antigen-presenting cells (APC), thymic epithelium
and B cells.
5.1.1
The MHC Class I Antigen-Processing Machinery (APM)
The molecular steps of the classical MHC class IAPM have been well characterized
during the last decade and appear to be more complex than initially expected
(Fig. 5.2) [4]. De novo synthesized MHC class Imolecules assemble in the endoplasmic
reticulum (ER) with peptides which have been yielded from mainly cytosolic
proteins by the multicatalytic proteasome complex or/and other cytosolic proteases
[5]. In normal untransformed cells the production of MHC class I peptide ligands by
the proteasome is an extremely inefficient process. The delivery of substrates to the
proteasome by the molecular chaperone HSC70 might trigger a modification in proteasomes
that favors the generation of MHC class Iligands [6]. The constitutive proteasome
subunits X, Y and Z are exchanged upon cytokine treatment by the proteasome
subunits low molecular weight protein (LMP) 2, LMP7 and LMP10. Their expression,
as well as the expression of the proteasome activators PA28a and b, can be
modulated by interferon (IFN)-g, tumor necrosis factor (TNF)-a, IFN-a as well as interleukin
(IL)-10. These inducible subunits are involved in the formation of the immunoproteasome.
Changes in the subunit composition sharpen the quantitative
and qualitative ability of the proteasome to generate antigenic peptides which limit
the production of self peptides. The antigenic peptides are then transported into the
ER by the ATP-dependent peptide transporter associated with antigen processing
(TAP). TAP, a member of the ABC transporter family, consists of the subunits TAP1
and TAP2, and selects peptides of certain length and specific sequence. Peptides
with a preferential length of 8±16 amino acids are efficiently translocated into the
ER [7]. TAP is a component of a large macromolecular peptide loading complex incorporating
TAP1, TAP2, tapasin as well as the MHC class IHC/b 2-m dimer in stoichiometrically
defined ratios. Tapasin represents a linker between TAP and the
MHC class Iheterodimer, ensuring high peptide-loading efficiency, optimal ligand