Transcript MHC Class II Molecules

Talk 5
T细胞受体与主要组织相容性
复合体分子
T-Cell Receptor and Major
Histocompatibility Complex Molecules
Overview
T cells recognize antigens that are presented by antigen
presenting cells (APCs) only
The way which TCR recognizes antigens is quite different
from antigen recognition by antibody (e.g. recognize antigen
fragments presented by MHC molecules only)
The most important antigen-presenting molecules are class I
and class II molecules of MHC, and more recently other
antigen-presenting molecules have been identified (e.g. CD1
presents lipid and glycolipid antigens)
However, antibody and TCR have many similarities, they are
structurally related (folded into Ig superfamily domains),
clonally distributed (each has a receptor with individual
specificity) and their receptors are generated by somatic
recombination (体细胞重组) from a limited number of germ
line (生殖系) genes
TCR:CD3 Complex
The  TCR heterodimer
forms the recognition unit
of the receptor
The CD3 complex
associates with the  or
γδforms of TCR
The γδTCR structurally
resemble the TCR
The external portion of
each chain consists of two
domains, resembling Ig
variable and constant
domains
TCR Gene and Expression
The organization of the gene
segments for TCR  and 
chains is generally homologous
to the L chain and H chain of
Ig gene segments, respectively
Like Ig genes in B cells, TCR
gene segments rearrange during
development to form complete
V-domain exons
The process takes place in the
thymus
TCR serves only for antigen
recognition and its constant
region genes are much simpler
Number and Diversity between TCR and
Ig Gene Segments
TCR diversity is focused in CDR3. Somatic hypermutation is not a major
mechanism for generating diversity in TCR
Major Histocompatibility Complex Molecules
The gene complex was first identified based on the ability of a
donor to accept grafts from the recipient sharing the same MHC
hapotype
MHC contains >100 gene loci, but only class I and class II
molecules determine graft rejection and present antigens
MHC class I and II molecules are highly polymorphic cellsurface glycoproteins
The gene complex in mouse is called H-2 and in human
leukocyte antigen (HLA) system
The remaining genes in MHC are very diverse, including genes
coding for complement components (C4, C2 and factor B),
cytokines, enzymes, heat-shock proteins and other molecules
involved n antigen processing, which are collectively called
class III genes
Overall Organization of MHC
• Three human class I loci, two or three mouse class I loci;
• Human class II genes are located in the HLA-D region, while
murine class II genes are located in the H-2I region
MHC Class I Molecules
Consist of an MHC-encoded
heavy chain bound toβ2microglobulin
β2-microglobulin is essential
for expression of MHC class
I molecules
Heavy chain α1 and α2
domains form the antigenbinding groove
Variations in amino acid
sequence change the shape
of the binding groove
MHC Class II Molecules
The overall structure resembles class I molecules
Interactions of MHC Molecules with
Antigenic Peptides
T cells recognize the
appropriate MHC molecule
bound-peptides only
In a MHC class I molecule,
the bound peptide is
surrounded by the two 
helices from 1 and 2
domains
In a MHC class II
molecule, the peptide is
held between the  helices
of the 1 and 1 domains
Interactions of MHC Molecules with
Antigenic Peptides
MHC class II binding groove accommodates longer peptides
than class I
Peptides are held in the binding cleft by characteristic anchor
residues
The length of Peptides Bound by MHC
Class II Molecules
The peptide lies in an extended
conformation along the
peptide-binding groove
In principle, no upper limit on
the length of peptides binding
to the molecules, but longer
peptides are trimmed by
peptidases to 13-17 amino
acids in most cases
Amino acid side chains at
residues 1, 4, 6, and 9 of a
minimal MHC class II-bound
peptide are held in the binding
pockets
It is more difficult to detect a
peptide-binding motif for MHC
class II molecules
MHC Polymorphism Affects Antigen
Recognition
Individual MHC molecules
can differ by up to 20 amino
acids
Most of the differences are on
the surfaces of the outer
domain, the peptide-binding
groove in particular
 Different allelic variants of
MHC molecules bind different
peptides
Previously called immune
response (Ir) gene encodes
MHC class II molecules
• Polymorphism of MHC
molecules guarantees
sufficient MHC molecules to
avoid non-responsiveness
Distribution of MHC Molecules
Different distribution of MHC
Tissue
molecules reflects the functions
Lymphoid
of T cells
tissue
Class I molecules present
T cell
intracellular antigenic peptides
B cell
+
to CD8 Tc cells，inducing
Macrophage
cellular immune response (CTL) Other APC
The main function of CD4+ T
Other cells
cells is to activate other effecter
Neutrophil
cells and thus MHC class II
Liver
molecules are present mainly on
Kidney
APC
Brain
The expression levels of MHC
molecule influence activation of
T cells
MHC I MHC II
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Interaction of TCR with MHCBound Antigens
Aggregation of TCRs
initiates T-cell
activation
Antigenic peptides can
induce or antagonize
T-cell activation
CD4 and CD8 are coreceptors of TCR
APC
MHC I/II
CD8/4
TC
R
T
MHC Restriction
A T cell specific for MHCapeptidex will not recognize
MHCb-peptidex or MHCaantigeny
Co-recognition of peptide and
MHC molecule is known as
MHC restriction (the MHC
molecules restrict the ability of
the T cell to recognize antigen)
The restriction may result from
direct contact between MHC
molecule and TCR or indirect
effect of MHC polymorphism
on the peptides