1
Introduction
1
Introduction
1.1
The major histocompatibility complex
The major histocompatibility complex (MHC; human leukocyte antigen (HLA)
complex in humans) is a highly polymorphic region on chromosome 6 in humans with
genes that encode MHC molecules that play a fundamental role in the immune system
and autoimmunity (figure 1.1). For example, lack of expression of MHC class II
(MHC II) molecules results in severe immunodeficiency with defects in both cellular
and humoral immunity causing extreme vulnerability to infections (Reith and Mach,
2001). Genetic susceptibility to many autoimmune diseases, including multiple sclerosis
and rheumatoid arthritis, has been linked directly to the MHC II locus (Goronzy and
Weyand, 2005; Svejgaard, 2008). The MHC first received attention in the context of
tissue and organ transplantation studies which showed that this locus was involved in
graft acceptance and rejection (histocompatibility).
The class I molecules are expressed in most nucleated cells where they present
mainly endogenous peptides on the cell surface to effector cells such as CD8+ T cells
(cytotoxic T lymphocytes). The presented peptide repertoire can be derived from either
normally-expressed self proteins or microbial proteins in the case of an infected cell.
Presentation of pathogen-derived peptide by MHC class I molecule to an effector cell
allows for recognition and killing of the infected cell, while presentation of normal self-
peptide induces tolerance.
In comparison, the class II molecules (HLA-DR, -DQ and -DP) are presented on
specialized antigen presenting cells including macrophages, dendritic cells and B cells.
During infection MHC II molecules present exogenous peptides to CD4+ T cells
derived from extracellular pathogens. Upon recognition of pathogenic peptides CD4+ T
cells activate and direct other immune cells to the site of inflammation and therefore
play a crucial role in initiating an adequate immune response. Both MHC class I and II
molecules show extensive sequence polymorphisms especially in the peptide-binding
region allowing different types of peptides to bind (Germain, 1994).
The MHC III region, also called central MHC, as it is flanked by the centromeric
MHC II and the telomeric MHC I genes, is less polymorphic and encodes protein
families involved in various aspects of innate immunity (complement proteins,
2
Introduction
inflammatory cytokines, and heat shock proteins) as well as some proteins not directly
involved in the immune system (Hauptmann and Bahram, 2004).
Figure 1.1: Schematic representation of the HLA locus on chromosome 6 in humans. The HLA
region is located on the short arm of chromosome 6 from 6p21.1 to p21.3 indicated by a red bar. T he
extent of the class II (red), class III (blue) and class I (green) genes that spans from the centromeric (cen)
to the telomeric (tel) end is shown. The class II region includes the genes for α and ß chains of the MHC
class II molecules HLA-DR, -DP, and -DQ. In addition, the genes encoding the DMα and DMß chains,
and the genes encoding α and ß chains of the DO molecule (DNα and DOß, respectively) are also located
in the MHC class II region (adapted from (Mehra and Kaur, 2003)).
1.2
MHC class II dependent pathway of antigen presentation
Like other cell-surface glycoproteins, MHC class I (MHC I) and MHC class II
(MHC II) molecules assemble in the endoplasmic reticulum (ER). As shown in figure
1.2, unlike MHC I molecules which bind endogenous peptides in the ER, MHC II
molecules must protect their peptide-binding site until they reach the late endosomal
compartment where they bind exogenous peptides. Therefore the α- and β- subunits
which form the MHC II molecule associate with a third molecule, the MHC class II-
associated invariant chain (Ii), which partially binds to and occludes the peptide-binding
groove. In the ER lumen the invariant chains first form a trimer and successively three
MHC II α/β- heterodimers bind noncovalently to each subunit (Lamb and Cresswell,
1992) with the chaperone calnexin binding and stabilizing the different components
(Anderson and Cresswell, 1994). After assembly, the nonameric complex is directed
through the Golgi apparatus to a low pH endosomal compartment via a signal sequence
in the cytoplasmic region of the invariant chain. The main site of peptide loading in the
MHC II pathway is the endocytic MHC class II-containing compartment (MIIC)
(Anderson and Cresswell, 1994). During transport and within these late endocytic, early
3
Introduction
lysosomal structures, the invariant chain is gradually cleaved by lysosomal proteases
(Cresswell, 1996; Newcomb and Cresswell, 1993; Roche et al., 1991) such as the
cysteine proteases cathepsins S and L (Deussing et al., 1998; Nakagawa et al., 1998;
Riese et al., 1996). After initial C-terminal truncation of the invariant chain, further
degradation leaves only short peptide fragments, called CLIP (class II-associated
invariant-chain peptides), bound to MHC II molecules. As CLIP binds in the peptide-
binding groove of MHC II molecules, it must be removed in order for other antigenic
peptides to bind and later on to be presented on the cell surface.
HLA-DM (DM), another transmembrane protein also encoded in the MHC and
regulated by the class II transcriptional transactivator (CIITA) like MHC II molecules,
undertakes the task of peptide exchange and plays an important role in the process of
peptide loading and formation of stable MHC II/peptide complexes. Forming stable
complexes between MHC II molecules and peptides is crucial for a specific immune
response as these complexes can be present on the cell surface for days (Lanzavecchia
et al., 1992). During this time peptide loss due to weak interactions and binding of
locally available peptides outside the cell by empty MHC II molecules could lead to
ineffective and uncontrolled peptide presentation. The important function and activity of
DM will be further discussed in section 1.4.
In uninfected cells, similar to MHC I molecules, MHC II molecules bind peptides
derived from self proteins, frequently originating from aggregated and degraded
MHC II and invariant chain molecules (Vogt et al., 1994). In case of infection MHC II
molecules present exogenous peptides derived from internalization of pathogens and
pieces of pathogenic organisms or eukaryotic parasites residing in intracellular vesicles.
The loaded peptides are products of proteolytic degradation by proteases that are
activated at low pH in the late endosomes and lysosomes. Among these proteases are
the cysteine proteases cathepsins B, D, S, and L whereas cathespsins S and L are most
predominant. There are also other proteases involved in antigen processing and the
overall peptide repertoire presumably reflects the activities of the many proteases that
are present in the endosomal pathway.
After forming stable MHC II/peptide complexes the molecules are transported to the
cell surface where bound peptides are presented to T cell receptors (TCR) which are
present on T cells. As T cell recognition of antigens is MHC restricted, the TCR has to
recognize the peptide and the specific MHC II molecule. In order to achieve full
activation of a naïve T cell, the activated antigen presenting cell must also provide
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