|
Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical
Design
Volume 15, Number 28, 2009
Contents
MHC and MHC-Like Molecules in the Design of Vaccines
Executive Editor: Vasso Apostolopoulos
Editorial: Pp. 3207-3208
[PMID:
19860670 PubMed - indexed for MEDLINE]
Prediction of MHC-Peptide Binding: A Systematic and Comprehensive
Overview Pp. 3209-3220
Esther M. Lafuente and Pedro A.
Reche
[Abstract] [Full
Text Article]
[PMID:
19860671 PubMed - indexed for MEDLINE]
Characterization of MHC Ligands for Peptide
Based Tumor Vaccination Pp. 3221-3236
Felix Klug, Matthias Miller, Hans-Henning
Schmidt and Stefan Stevanovic
[Abstract] [Purchase
Article]
[PMID:
19860672 PubMed - indexed for MEDLINE]
Models of Antigen Receptor Activation
in the Design of Vaccines Pp. 3237-3248
Eszter Molnár,
Elaine-Pashupati Dopfer, Sumit Deswal and Wolfgang
W.A. Schamel
[Abstract]
[Purchase
Article]
[PMID:
19860673 PubMed - indexed for MEDLINE]
HLA-DR: Molecular Insights and Vaccine Design Pp.
3249-3261
Lawrence J. Stern and J. Mauricio
Calvo-Calle
[Abstract] [Purchase
Article]
[PMID:
19860674 PubMed - indexed for MEDLINE]
Use of MHC II Structural Features in
the Design of Vaccines for Organ-Specific Autoimmune Diseases
Pp. 3262-3273
Antonis K. Moustakas and George
K. Papadopoulos
[Abstract] [Purchase
Article]
[PMID:
19860675 PubMed - indexed for MEDLINE]
Non-Canonical Peptides Bound to MHC Pp.
3274-3282
Stephanie L. Day, Paul A. Ramsland and
Vasso Apostolopoulos
[Abstract] [Purchase
Article]
[PMID:
19860676 PubMed - indexed for MEDLINE]
''Self-Nonself”
Peptides in the Design of Vaccines Pp. 3283-3289
Darja Kanduc
[Abstract] [Purchase
Article]
[PMID:
19860677 PubMed - indexed for MEDLINE]
The TCR/CD3 Complex: Opening the Gate
to Successful Vaccination Pp. 3290-3300
Pilar Portolés
and Jose M. Rojo
[Abstract] [Purchase
Article]
[PMID:
19860678 PubMed - indexed for MEDLINE]
NK Cell Receptors and Their Interactions
with MHC Pp. 3301-3310
Roberto Biassoni, Elisabetta Ugolotti and
Andrea De Maria
[Abstract] [Purchase
Article]
[PMID:
19860679 PubMed - indexed for MEDLINE]
Presentation of Lipid Antigens by CD1
Glycoproteins Pp. 3311-3317
André
Schiefner and Ian A. Wilson
[Abstract] [Purchase
Article]
[PMID:
19860680 PubMed - indexed for MEDLINE]
HLA-G Molecule Pp. 3318-3324
Jun Kamishikiryo and Katsumi Maenaka
[Abstract] [Purchase
Article]
[PMID:
19860681 PubMed - indexed for MEDLINE]
HPLC and MS Analysis for the Identification
and Characterisation of Peptides Presented in the Context
of the Non-Classical Human Leukocytes Antigen (HLA) Class
I Molecule HLA-E Pp. 3325-3335
Enrico Millo and Gianluca Damonte
[Abstract] [Purchase
Article]
[PMID:
19860682 PubMed - indexed for MEDLINE]
HLA-E and HLA-E-Bound Peptides: Recognition
by Subsets of NK and T Cells Pp. 3336-3344
Gabriella Pietra, Chiara Romagnani, Lorenzo
Moretta and Maria Cristina Mingari
[Abstract]
[Purchase
Article]
[PMID:
19860683 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[PMID:
19860670 PubMed - indexed for MEDLINE]
Editorial: MHC and MHC-Like Molecules in the Design
of Vaccines
CLASSICAL MHC CLASS I, CLASS II AND CLASS III MOLECULES
The major histocompatibility complex (MHC) predominantly
expressed on the surface of antigen presenting cells, present
short peptide fragments from antigens to T cells. The MHC
is divided into 3 subgroups, MHC class I, MHC class II and
MHC class III.
MHC class I encodes heterodimeric peptide binding proteins,
in addition to antigen processing molecules such as tapasin
and TAP. MHC class I consists of 3 gene families, for murine
MHC class I, H-2K, H-2D and H-2L and for human MHC class I,
HLA-A, HLA-B, HLA-C. Short peptide fragments are presented
by MHC class I to CD8+ T cells. The first crystal structure
of an MHC class I molecule was the human HLA-A2. Twenty years
later, more than 170 crystal structures of peptide-MHC class
I structures have been determined, which include, human HLA-A1,
HLA-A2, HLA-A3, HLA-A11, HLA-B27, HLA-A31 HLA-Aw68, HLA-B35,
HLA-B53, HLA-B44, HLA-57, and murine H-2Kb,
H-2Db, H-2Ld
and H-2Kk.
The H-2 and HLA genes consist of a heavy chain and a light
chain (β2-microglobulin).
The heavy chain anchors the MHC class I into the cell membrane
and is divided into 3 domains (α1,
α2,
α3).
Short peptide fragments bind into a peptide binding groove
which is located between the α1
and α2
helices. The structural data has aided in the interpretation
of immunological data and has been of benefit in the design
of peptide based vaccines against many diseases.
MHC class II encodes heterodimeric peptide binding proteins
and proteins that modulate peptide loading onto MHC class
II proteins in the lysosomal compartment such as MHC class
II DM, -DQ and -DP. MHC class II encodes the genes I-A and
I-E for murine and HLA-DP, HLA-DQ and HLA-DR for human (HLA-DPA1,
-DPB1, -DQA1, -DQB1, -DRA, -DRB1). Peptide fragments, usually
longer than MHC class I, are presented by MHC class II to
CD4+ T cells. The first crystal structure of MHC class II
was the human HLA-DR1. Sixteen years later structures of HLA-DR3,
HLA-DR4, I-Ek, I-Ad,
I-Ak, I-Ag7
etc have been determined. MHC class II comprises an α-chain
(α1
, α2)
and β-chain
(β1
, β2).
Peptides bind into a peptide binding groove (cleft) which
is located between the α1
and β1
helices. The peptide binding cleft is open, thus accommodating
longer amino acids than MHC class I, usually, 13-18 residues.
MHC class III encodes for other immune components, such as,
complement (C2, C4a, factor B, Bf), cytokines (TNF-α,
TNF-β and
lymphotoxin), HSP70, enzymes for steroid synthesis, and, numerous
other unidentified protesin. MHC class III is important in
immune regulation and inflammation. MHC class III molecules
do not binding or present antigenic peptides.
NON-CLASSICAL MHC / MHC-LIKE MOLECULES
Studies in the last decade have shown that numerous different
antigens can be recognized by the TCR, such as the non-classical
MHC molecules. The MHC class I molecules are subdivided into
2 families, (i) the classical MHC class I (class Ia) and (ii)
the non-classical MHC class 1 molecules (class 1b). Murine
and human MHC class Ia is highly polymorphic, whereas, MHC
class Ib molecules show slight allelic variation. The MHC
class Ib family members include H-2M, H-2Q and H-2T in mouse
and HLA-E, HLA-F, HLA-G and HFE (HLA-H) in humans. The non-classical
MHC class Ib molecules play a major role in innate immunity
and in adaptive immunity regulating immunity to viruses, bacteria,
tumors and self antigens. The crystal structures for HLA-E,
HLA-G, H-2Q9, H-2M3 and HFE have been determined. The overall
basic framework closely resembles that of MHC class Ia molecules.
MHC class Ib molecules consist of a heavy chain (α1,
α2,
α3
helices) which is associated with the light chain, β2
microglobulin. Peptides bind between the α1
and α2
helices. The ability of CD8 T cells to recognize both MHC
class Ia and class Ib molecules, suggests a common ancestry
between these two molecules. It is possible to develop vaccines
based on MHC class Ib restricted responses, however, the advantage
of such vaccines remain to be determined. The non-classical
MHC class II molecules include, HLA-DM and HLA-DO (or H-2DM
and H-2-O in the mouse). HLA-DM stabilizes empty MHC class
II molecules in lysozomes / endosomes until peptides are available
to bind by exchanging with CLIP (invariant chain derived peptides).
HLA-DO associates with HLA-DM and aids in the down-regulation
of HLA-DM and is an important modulator of MHC class II restricted
antigen processing.
MHC class I-like molecules interact with CD8 T cells, NK cells
or γδ
T cells. Structural and immunological studies of the MHC class
I-like molecules, T10, T22, FcRn, CD1 and the stress induced
MICA, MICB, ULBP, Rae1, H60, have given insights of their
role and importance in the immune response. The expression
of CD1 molecules is independent of TAP, however, it localizes
in MHC class II compartments (late endosomes/lysosomes) where
they bind to exogenous antigens. The CD1 family is divided
into two groups in humans, group I - CD1a, CD1b and CD1c isotypes
and group II - CD1d; CD1e has an intermediate isotype. The
CD1 in mice is less complex, with only 2 closely related genes,
CD1d1 and CD1d2, and are members of group II subfamily. The
CD1d isotype is completely preserved in human, mouse, rabbit
and rat. CD1 molecules are involved in presenting lipid antigens
to T / NK cells. Immunological data and crystal structures
of some of the MHC like molecules have provided vital information
of how the immune system presents antigens, and may assist
in the design of vaccines using or targeting these molecules.
MHC AND MHC-LIKE MOLECULES IN THE DESIGN OF VACCINES
Increasing basic understanding of cellular immune responses
and crystal structures of how the immune system presents peptides
and how T cells recognize peptides are important in peptide-based
vaccine design. Structural insights into classical and non-classical
MHC class I and class II molecules, their interaction with
the TCR, the induction of glycopeptide specific T cells and
their structure, non-canonical modes of peptide binding to
MHC class I molecules and the identification and crystal structures
of MHC-like molecules, have helped interpret immunological
data and has been of great benefit in drug design and development
of novel ligand-based vaccines against many diseases.
In a timely manner, this ‘hot
topic issue’
on MHC molecules is up-to-date on the immunological and structural
features of such molecules and gives insights of the development
of peptide based vaccines. The article by Reche et al.
[1] gives an overall review on predicting peptides which bind
to MHC. Stevanovic and colleagues [2] give a nice overview
of the characterization of peptides which bind to MHC based
on tumor vaccines. Schamel et al. [3] presents models
of antigen receptor activation in the design of vaccines.
Stern et al. [4] introduces MHC class II and its
role in vaccine design and Papadopoulos et al. [5]
presents MHC class II structural features in the design of
vaccines for autoimmune diseases. Apostolopoulos et al.
[6] introduces peptides which bind to MHC class I or class
II molecules in a non-canonical manner and Kanduc [7] describes
the differences between self and non-self in the design of
vaccines. Rojo et al. [8] opens the gate for vaccination
using information from TCR/CD3 complexes. Biassoni and colleagues
[9] introduces the interactions of NK cells with MHC molecules,
Wilson et al. [10] presents nice data on lipid antigens
by CD1 glycoproteins, Maenaka et al. [11] presents
data on the HLA-G molecule and Millo et al. [12]
and Moretta et al. [13] give insights of HLA-E and
its role in presenting peptides and its use for the design
of vaccines.
There is a plethora of information already available, and,
in the next 5 years, more information will become available
both immunologically and structurally on classical and non-classical
MHC molecules and MHC-like molecules. All the information
together, will aid in a better understanding of antigen presentation
and will aid in the design of more effective peptide-based
vaccines.
REFERENCES
[1] Lafuente EM, Reche PA. Prediction of MHC-peptide binding.
Curr Pharm Des 2009; 28: 3209-3220.
[2] Klug F, Miller M, Schmidt HH, Stevanovic S. Characterization
of MHC ligands for peptide based tumor vaccination. Curr Pharm
Des 2009; 28: 3221-3236.
[3] Molnar E, Dopfer E-P, Deswal P, Schamel W. Models of antigen
receptor activation in the design of vaccines. Curr Pharm
Des 2009; 28: 3237-3248.
[4] Stern L, Calvo-Calle JM. HLA-DR: Molecular insights and
vaccine design. Curr Pharm Des 2009; 28: 3249-3261.
[5] Moustakas AK, Papadopoulos G. Use of MHC II structural
features in the design of vaccines for organ-specific autoimmune
diseases. Curr Pharm Des 2009; 3262-3273.
[6] Day S, Apostolopoulos V. Non-canonical peptides bound
to MHC. Curr Pharm Des 2009; 28: 3274-3282.
[7] Kanduc D. Self - Nonself peptides in the design of vaccines.
Curr Pharm Des 2009; 28: 3283-3289.
[8] Rojo JM, Portoles P. The TCR/CD3 complex: Opening the
gate to successful vaccination. Curr Pharm Des 2009; 28: 3290-3300.
[9] Biassoni R, Ugolotti E, De Maria A. NK cell receptors
and their interactions with MHC. Curr Pharm Des 2009; 28:
3301-3310.
[10] Schiefner A, Wilson IA. Presentation of lipid antigens
by CD1 glycoproteins. Curr Pharm Des 2009; 3311-3317.
[11] Kamishikiryo J, Maenaka K. HLA-G molecule. Curr Pharm
Des 2009; 28: 3318-3324.
[12] Millo E, Damonte G. HPLC and MS analysis for the identification
and characterisation of peptides presented in the context
of the non-classical HLA class I molecule HLA-E. Curr Pharm
Des 2009; 28: 3325-3335.
[13] Pietra G, Romagnani C, Moretta L, Mingari MC. HLA-E and
HLA-E bound peptides: recognition by subsets of NK and T cells.
Curr Pharm Des 2009; 28: 3336-3344.
Vasso Apostolopoulos
Professor Head Immunology and Vaccine Lab
Burnet Institute,
Centre for Immunology
85 Commercial Road,
Prahran, VIC 3004
Tel: +613 9282 2111
Fax: +613 9282 2100
E-mail: vasso@burnet.edu.au
[Back to top]
[Full
Text Article]
[PMID:
19860671 PubMed - indexed for MEDLINE]
Prediction of MHC-Peptide Binding: A Systematic and Comprehensive
Overview
Esther M. Lafuente and Pedro A.
Reche
T cell immune responses are driven by the recognition
of peptide antigens (T cell epitopes) that are bound to major
histocompatibility complex (MHC) molecules. T cell epitope
immunogenicity is thus contingent on several events, including
appropriate and effective processing of the peptide from its
protein source, stable peptide binding to the MHC molecule,
and recognition of the MHC-bound peptide by the T cell receptor.
Of these three hallmarks, MHC-peptide binding is the most
selective event that determines T cell epitopes. Therefore,
prediction of MHC-peptide binding constitutes the principal
basis for anticipating potential T cell epitopes. The tremendous
relevance of epitope identification in vaccine design and
in the monitoring of T cell responses has spurred the development
of many computational methods for predicting MHC-peptide binding
that improve the efficiency and economics of T cell epitope
identification. In this report, we will systematically examine
the available methods for predicting MHC-peptide binding and
discuss their most relevant advantages and drawbacks.
[Back to top]
[Purchase
Article] [PMID:
19860672 PubMed - indexed for MEDLINE]
Characterization of MHC Ligands for Peptide Based Tumor Vaccination
Felix Klug, Matthias Miller, Hans-Henning
Schmidt and Stefan Stevanovic
Short peptides derived from cellular proteins may
escape complete destruction during protein catabolism and
finally serve as a showcase in the immune system. Exposed
at the cell surface to scrutiny by T cells, MHC:peptide complexes
mediate a highly specific and immediate information transfer
from diseased cells to the cellular immune system. Numerous
clinical vaccination trials have been carried out employing
MHC-presented peptides for T-cell activation with encouraging
results but so far without a final breakthrough. In this review,
we briefly highlight the molecular basis of MHC-peptide interactions
governed by specificity pockets and anchor residues, as summarized
in allele-specific peptide motifs. State-of-the-art technology
is comprehensively presented and gives an overview of modern
mass spectrometric strategies used for qualitative and quantitative
analysis of MHC ligands. We describe the details of the HLA-B*3801
peptide motif by comparing features of natural MHC ligands,
resulting in a scoring matrix that enables epitope prediction
from any viral or tumor antigen. The pronounced individuality
in peptide presentation by MHC molecules, as reflected in
the highly specific peptide motifs of different MHC allotypes
or the tissue-specific MHC ligandomes, represents a current
area of interest within this field. Finally, the identification
of post-translational modifications - most important phosphorylations
- and the promises this holds will be discussed in this chapter.
[Back to top]
[Purchase
Article] [PMID:
19860673 PubMed - indexed for MEDLINE]
Models of Antigen Receptor Activation in the Design of Vaccines
Eszter Molnár,
Elaine-Pashupati Dopfer, Sumit Deswal and Wolfgang
W.A. Schamel
Vaccination techniques have developed rapidly over the
last several decades from the immunization with live attenuated
pathogens to the use of peptide and DNA subunit vaccines,
from the use of classical adjuvants to cell-directed delivery.
Vaccination techiques are also under investigation for the
treatment of tumors and autoimmune diseases. However, profound
knowledge of activation mechanisms of the immune cells on
a molecular level is prerequisite for a better understanding
of the immune response, and for the development of effective
immunomodulatory tools. In this review we discuss the models
of BCR and TCR activation, and using the example of some vacciantion
technologies, we show, how the understanding of these models
could help in the design of a new generation of vaccines.
[Back to top]
[Purchase
Article]
[PMID:
19860674 PubMed - indexed for MEDLINE]
HLA-DR: Molecular Insights and Vaccine Design
Lawrence J. Stern and J. Mauricio
Calvo-Calle
Vaccines are one of the most cost effective methods to
control infectious diseases and at the same time one of the
most complex products of the pharmaceutical industry. In contrast
to other drugs, vaccines are used mainly in healthy individuals,
often in children. For this reason, very high standards are
set for their production. Subunit vaccines, especially peptide
vaccines, can provide a safe and cost-effective alternative
to vaccines produced from attenuated or inactivated pathogen
preparations. Biochemical and structural studies of class
II MHC - peptide complexes are beginning to provide a conceptual
foundation for the rational design of subunit and peptide
vaccines. In this review, we show how analysis of peptide-class
II MHC complexes together with developing understanding of
antigen processing pathways has opened the door to understanding
the major rules that govern selection of T cell epitopes.
We review progress towards computational prediction of such
epitopes, and efforts to evaluate algorithms that incorporate
various structural and/or biochemical aspects of the MHC-peptide
interaction. Finally, using malaria as a model, we describe
the development of a minimal subunit vaccine for the human
malaria parasite Plasmodium falciparum.
[Back to top]
[Purchase
Article] [PMID:
19860675 PubMed - indexed for MEDLINE]
Use of MHC II Structural Features in the Design of Vaccines
for Organ-Specific Autoimmune Diseases
Antonis K. Moustakas and George
K. Papadopoulos
The Major Histocompatibility Complex Class II locus is
the primary genetic linkage to autoimmune diseases. Susceptibility
to each such disease is linked to different alleles, with
a few alleles showing also dominant protection. The design
of vaccines for autoimmune diseases is a long sought-after
goal. As knowledge about the pathogenesis of these diseases
has increased, the tools for such an approach have of necessity
been refined. We review below the structural essence of MHC
II-linked autoimmune diseases which centers on the binding
of antigenic peptides to the disease-linked MHC II proteins,
and the consequent activation of cognate TCRs from pathogenic
CD4+ T cells. The state
of affairs in two organ-specific autoimmune diseases, type
1 diabetes, celiac disease are covered, including attempts
to treat these via antigen-specific MHC II-guided measures.
We offer a couple of testable suggestions as to how this approach
could be improved.
[Back to top]
[Purchase
Article] [PMID:
19860676 PubMed - indexed for MEDLINE]
Non-Canonical Peptides Bound to MHC
Stephanie L. Day, Paul A. Ramsland and
Vasso Apostolopoulos
Central to the initiation of a T cell dependent immune
response is the recognition of major histocompatibility complex
(MHC) class I or class II molecules (in humans termed HLA
and in mice termed H-2) bound to antigenic peptide. T cell
receptors (TCR) have programmed specificity for particular
peptide/MHC complexes, which ensures focused immune responses
are generated against the antigen source. To design effective
peptide based vaccines a comprehensive understanding of the
specific interactions between MHC molecules and peptide, and
of TCR recognition of MHC/peptide is valuable. We place particular
emphasis on non-canonical bound peptides and their use in
immunotherapy studies.
[Back to top]
[Purchase
Article] [PMID:
19860677 PubMed - indexed for MEDLINE]
''Self-Nonself”
Peptides in the Design of Vaccines
Darja Kanduc
What makes a peptide an epitope? This is a central question
in immunology. The clear identification of precise molecular
characteristics of epitopes would help define the basic mechanisms
of self/non-self distinction and lead to a greater understanding
of phenomena such as tolerance, autoimmunity, allergy, and
tumor escape of immune surveillance. Importantly, clarifying
the properties an epitope is paramount to the development
of diagnostic and therapeutic vaccines. This review analyzes
recent reports on experimentally identified B cell epitopes
associated with multiple infectious disease pathologies, cancer,
autoimmunity, hypertension, obesity, and allergy. It illustrates
data that further support the notion that only a low level
of sequence similarity to the host proteome is needed to modulate
the B cell epitope-specific peptidome. Amino acid sequences
that are unique to the antigen and are not shared with the
host proteome are specifically targeted by the humoral immune
response. Therefore, low-similarity peptides may be significant
to the rational development of peptide-based clinical treatments
in cancer, autoimmunity, infection, and allergy. Biologically,
the low-similarity hypothesis further supports sequence uniqueness
as the molecular signature of “nonselfness”
in the currently ongoing self/non-self debate.
[Back to top]
[Purchase
Article] [PMID:
19860678 PubMed - indexed for MEDLINE]
The TCR/CD3 Complex: Opening the Gate to Successful Vaccination
Pilar Portolés
and Jose M. Rojo
The success of vaccination is directly or indirectly
based on the specificity of antigen recognition by T lymphocytes,
their efficient activation and expansion, and the generation
of vaccine-specific effector and memory cells. These traits
are largely dependent on the correct assembly and expression
of sufficient number of functional TCR/CD3 complexes in the
cell surface. In this review, some of the genetic and epigenetic
factors that determine the correct assembly and structure
of the TCR/CD3 complex are summarized. Those physiologic or
pathologic factors leading to natural variations, or pathologic
alterations of the standard that might lead to poor response
to vaccination and that could give some possibilities to pharmacological
intervention are emphasized.
[Back to top]
[Purchase
Article] [PMID:
19860679 PubMed - indexed for MEDLINE]
NK Cell Receptors and Their Interactions with MHC
Roberto Biassoni, Elisabetta Ugolotti and
Andrea De Maria
MHC-specific Natural Killer inhibitory receptors display
a conserved and fundamental function in the regulation of
NK-mediated cytolysis. Their importance is substantiated by
the fact that during speciation different molecular receptor
structures have evolved to maintain inhibitory regulation
of NK cells. The information gained during these last twenty
years begins to be fruitfully used in the therapy of leukemias,
but a lot has to be still done. In particular, we need to
understand the role of activating KIR and their ligand(s),
since their role in the course of different viral diseases
is still intriguing.
[Back to top]
[Purchase
Article] [PMID:
19860680 PubMed - indexed for MEDLINE]
Presentation of Lipid Antigens by CD1 Glycoproteins
André
Schiefner and Ian A. Wilson
CD1 molecules are a family of non-polymorphic, class
I antigen-presenting glycoproteins, which bind and present
amphiphilic lipid antigens for recognition to T cells. Two
groups of CD1 molecules are involved in presentation of self
and foreign lipid antigens: group 1 (CD1a, CD1b and CD1c)
and group 2 (CD1d). Crystal structures of CD1a, CD1b and CD1d
in complex with different ligands have revealed the key principles
of lipid presentation and defined unique binding groove architectures
for the individual CD1 isoforms, which enable binding and
presentation of an enormous variety of lipids. Structural
and biochemical insights into presentation of glycolipids
by CD1d have led to the discovery of novel lipid antigens
and to a broader understanding of the underlying structural
and mechanistic principles of NKT cell stimulation. Some of
these glycolipids show enhanced and more specific stimulatory
properties and crystal structures have suggested further design
strategies for elicitation of immuno-stimulatory compounds
that may enable selective control of the secretion of regulatory
T helper cytokines.
[Back to top]
[Purchase
Article] [PMID:
19860681 PubMed - indexed for MEDLINE]
HLA-G Molecule
Jun Kamishikiryo and Katsumi Maenaka
Human leukocyte antigen-G (HLA-G) is a non-classical
HLA class I molecule, which was first discovered in 1987 by
Geraghty and colleagues [1]. While classical HLA class I molecules
are expressed on all nucleated cells, the expression of the
HLA-G molecule is highly tissue-restricted, such as to placental
trophoblast cells. HLA-G binds inhibitory receptors such as
leukocyte immunoglobulin-like receptors B1 (LILRB1/ILT2/CD85j)
and LILRB2 (ILT4/CD85d), which are widely expressed on immune
cells, to suppress a broad range of immune responses [2-4].
Thus, the expression of HLA-G in placenta protects the fetus
from the maternal immune system. On the other hand, emerging
studies have shown the relevance of the HLA-G molecule in
pathologic conditions, such as transplantation rejection,
autoimmunity, and cancer.
HLA-G has other unique characteristics, in contrast with classical
HLA molecules, including the existence of various forms of
HLA-G: several splice variants, subunit-deficient conformations,
homodimers, and their combinations have been found [5]. In
this review, we highlight the molecular basis for the tolerogenic
ability of the HLA-G molecule, especially by LILR recognition
of various forms of HLA-G. We also discuss the potential clinical
applications of HLA-G molecules.
[Back to top]
[Purchase
Article] [PMID:
19860682 PubMed - indexed for MEDLINE]
HPLC and MS Analysis for the Identification and Characterisation
of Peptides Presented in the Context of the Non-Classical
Human Leukocytes Antigen (HLA) Class I Molecule HLA-E
Enrico Millo and Gianluca Damonte
In addition to a variety of other techniques used in
T-cell epitope identification, mass spectrometery coupled
to liquid chromatography have now become an important and
sensitive tool in separation, detection, and sequence analysis
of highly complex natural major histocompatibility complex
(MHC) ligand mixtures. In this article, we present current
strategies for the identification of MHC eluted peptides using
high-performance liquid chromatography coupled to tandem mass
spectrometry (HPLC-MS/MS) with a particular recall to those
presented in the context of the non classical human leukocytes
antigen (HLA) class I molecule HLA-E.
In addition we also discuss the advantages and disadvantages
of the methods available in the literature to concentrate
and fractionate the peptides prior to analysis by mass spectrometry.
An application of our method for isolation and characterization
of peptides presented in the context of HLA-E is finally reported.
[Back to top]
[Purchase
Article]
[PMID:
19860683 PubMed - indexed for MEDLINE]
HLA-E and HLA-E-Bound Peptides: Recognition
by Subsets of NK and T Cells
Gabriella Pietra, Chiara Romagnani, Lorenzo
Moretta and Maria Cristina Mingari
In humans, major histocompatibility complex (MHC) class I
molecules comprise the classical (class Ia) human leukocyte
antigens (HLA)-A, -B, and -C, and the non-classical (class
Ib) HLA-E, -F, -G and –H
(HFE) molecules. The best-characterized MHC class Ib molecule
is HLA-E. HLA-E was first described as a non-polymorphic ligand
of the CD94/NKG2 receptors expressed mainly by natural killer
(NK) cells and its role was thus confined to the regulation
of NK cell function. Therefore, interaction of HLA-E with
the CD94/NKG2 receptors can result in either inhibition or
activation of NK cells, depending on the peptide presented
and on the NKG2 receptor CD94 is associated with. Thus, CD94/NKG2A
functions as an inhibitory receptor, whereas CD94/NKG2C functions
as an activating receptor. However, recent evidences obtained
by our group and others indicated that HLA-E represents a
novel restriction element for ab T-cell receptor (TCR)-mediated
recognition. Although HLA-E displays a selective preference
for nonameric peptides derived from the leader sequences of
various HLA class I alleles, several reports showed that it
can also present “non-canonical”
peptides derived from both stress-related and pathogen-associated
proteins. Because HLA-E displays binding specificity for innate
CD94/NKG2 receptors but also has the features of an antigen-presenting
molecule –
including the ability to be recognized by ab T cells –
it does appear that this MHC class Ib molecule plays an important
role in both natural and acquired immune responses.
|
