Transcript 7.4mb ppt - UCLA.edu

October 21, 2004
IMMUNITY
MHC
ADAPTIVE
INNATE
EFFECTOR SYSTEMS
Fc Receptors
Complement
CELL MEDIATED
TCR
HUMORAL
ANTIBODIES
ANTIGENS
BCR
Soluble Ab
RECEPTORS
EFFECTORS
Cells
Molecules
The Major Histocompatibility complex
(MHC)
HLA in human
H-2 in mice
The main barrier to organ transplatation
Role of the MHC:
Present Ag to T cells
B cellss interact with free native Ag in solution.
T cells only interact with Ag at
cell surfaces and the
requirement for co-recognition
of Ag and MHC ensures that this
happens
Class I MHC
Cell surface glycoprotein
Two chains:
45 kD transmembrane chain with carbohydrate
Non-covalently associated
13kD -2 microglobulin
-2 is not a transmembrane protein
Class II MHC
Found on a restricted number of cells
Usually B, M, dendritic
cells, sometimes T
Antigen presenting cells
Transmembrane  chain of 32 kD
Transmembrane chain of 27 kD
Within the cell it is associated with the
invariant chain, Ii
Class II MHC
Found on a restricted number of cells
Usually B, M, dendritic
cells, sometimes T
Antigen presenting cells
Transmembrane  chain of 32 kD
Transmembrane chain of 27 kD
Within the cell it is associated with the
invariant chain, Ii
Note contact of TCR with peptide
and MHC moleculeMHC RESTRICTION
Class I and Class II both Function to Present Antigen
Different Roles
Class I displays fragments of protein synthesized inside cell
If peptide is foreign, cell is killed by CD8 T cells
Expressed on all nucleated cells
Class II functions to display fragments of proteins from
outside the cell
Expressed only by proliferating APC
If peptide is foreign, CD4 T cells are activated
Help B cells
Inflammation
Genes of the MHC
HLA in hum an
Class I
-chain genes: HLA-A, -B, -C
-2 microglobulin encoded outside MHC
Class II - three pairs of - and - chain genes
HLA-DR: 
HLA-DP: 
HLA-DQ: 
TAP-1 and TAP-2 encode peptide transporter
LMP encodes com ponents of the proteasom e
DM resembles class II;
catalyzes peptide binding to
MHC
Class III - other genes in MHC,
some important in im mune function
C2, C4, Factor B, TNF- , TNF-
Variability
Tremendous polymorphism
Germline encoded
Extensive variation within species
For some MHC loci there are more 100 alleles
P
o
P
Polymorphism concentrated in amino acids lining the binding pocket
For Class II the polymorphisms are also concentrated
in the binding pocket with the -chain showing more
variability than the -chain
Extensive variation makes it
likely that the population will
possess alleles that recognize
every pathogen
Extensive Diversity Makes it Extremely
Unlikely that Two People are Identical at
their MHC Locus
If just consider HLA-A and B
If 50 alleles at each locus
There are 4 different molecules on the surface because
of co-dominant expression
Therefore odds of two people being
identical is 1 in (50)4 or 1/6,250,000
Remember also HLA-C
Also Class II
Expression
Class I there is co-dominant expression
Express all three genes of both chromosomes
Human
Amom and Adad
Bmom and B dad
Cmom and Cdad
Mouse
Kmom and Kdad
Dmom and Ddad
Lmom and L dad
Expression
Class I there is co-dominant expression
Express all three genes of both chromosomes
Human
Amom and Adad
Bmom and B dad
Cmom and Cdad
Mouse
Kmom and Kdad
Dmom and Ddad
Lmom and L dad
Expression
Class II also co-dominant expression on APCs
Mouse
IAmon and IAdad
IE mon and IE dad
Expression
Class II also co-dominant expression on APCs
Mouse
IAmon and IAdad
IE mon and IE dad
Because Class II is made up of two chains get
heterozygous complementation
IAkk IAkd IAdk IAdd
IEkk IEkd IEdk IEdd
Never mix  and  chains of IA and IE
Never IEIA
Expression
Codominant expression
Heterozygote complementation
Molecules with one chain from mom and one from dad
For example:
DP
Genes expressed
DP DPDP DP
DP DPDP DP
Proteins expressed
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
DPDP
Never get mixed molecules between isotypes
e.g. DRDQ
Class 1 b MHC Molecules
Limited polymorphism
Class 1 b MHC Molecules
CD1
Human CD1 is encoded by five
nonpolymorphic and closely
linked genes
CD1
CD1 proteins are able to present
non-peptide Ags to T cells
Ags have a hydrophobic lipid tail
and a hydrophilic end
T cells are specific for the
hydrophilic end
Hydrophobic tail appears to to insert
into hydrophobic pocket of CD1
Ags have a hydrophobic lipid tail
and a hydrophilic end
T cells are specific for the
hydrophilic end
Hydrophobic tail appears to to insert
into hydrophobic pocket of CD1
Glucose
monomycolate
Free
mycolate
Hydrophilic
Hydrophobic
Phosphoinositide
mannoside
Natural Killer (NK) Cells- Innate Immunity
Germline encoded receptors
Monitor the expression of cell surface
molecules that are dysregulated as a
consequence of pathologic changes within
cells
Initiate not only NK cytotoxicity but also
a general inflammatory response
Natural Killer (NK) Cells- Innate Immunity
Share a common early progenitor with T cells
Very important against virus infection and
tumors
No rearrangement of receptor so develop
in RAG- mice
Have granules containingperforin and
granzymes
Natural Killer (NK) Cells- Innate Immunity
Have two types of receptors:
Activating receptors that initiate killing
Inhibitory receptors that inhibit killing
Natural Killer (NK) Cells- Innate Immunity
Activating receptors that initiate killing
Are associated noncovalently with other
molecules containing ITAMs
Natural Killer (NK) Cells- Innate Immunity
Inhibitory receptors that inhibit killing
Contain one or two ITIM sequences that
when tyrosine phosphorylated recruit and
active SHP-1 and SHP-2phosphatases
Interact with class I molecules
Inhibitory receptors of particular specificity
expressed only by a subset of NK cells
Examples:
CD94/NKG2A is an inhibitory receptor. Its ligands include the
nonclassical MHC-I molecules HLA-E (human) and Qa-1 (mice).
These selectively
bind peptides from the leader sequence of MHC-I
heavy chains.
NKG2D is an activating receptor. It recognizes molecules that are
upregulated in stressed cells and overexpressed by epithelial tumors.
The balance between
inhibitory
signals from receptors specific for
MHC-I and stimulatory signals
mediated by a variety of activating
receptors ultimately determines the
outcomes of an NK cell - target cell
encounter
The inhibitory receptor CD94/NKG2A recognizes
HLA-E (human) and Qa-1 (mice). These selectively
bind peptides derived from the leader sequence of
MHC-1 heavy chains. Thus proper expression of
HLA-E or Qa-1 is an indictor of normal expression of
MHC-1 molecules.
To Cell Surface
5
2-m
signal peptide
MHC class I
ER Lumen
HLA-E
TAP
The inhibitory receptor CD94/NKG2A recognizes
HLA-E (human) and Qa-1 (mice). These selectively
bind peptides derived from the leader sequence of
MHC-1 heavy chains. Thus proper expression of
HLA-E or Qa-1 is an indictor of normal expression of
To Cell Surface
MHC-1 molecules.
5
2-m
signal peptide
MHC class I
ER Lumen
HLA-E
TAP
HLA-E
Untransfected
Killing by CD94/NKG2A+NK cells
+ pan anti-MHC class I
+ anti-HLA-E
+ anti-CD94
+ anti-HLA-C
+
n.a.
n.a.
n.a.
n.a.
HLA-C
Transfected Transfected w ith Exogenous
w ith HLA-C HLA Leader
Peptide Addition
+
+
+
-
+
+
+
-
+
+
+
-
To Cell Surface
5
2-m
signal peptide
ER Lumen
HLA-E
HLA-E
MHC class I
HLA-C
TAP
Untransfected
Killing by CD94/NKG2A+NK cells
+ pan anti-MHC class I
+ anti-HLA-E
+ anti-CD94
+ anti-HLA-C
+
n.a.
n.a.
n.a.
n.a.
Transfected Transfected w ith Exogenous
w ith HLA-C HLA Leader
Peptide Addition
+
+
+
-
+
+
+
-
+
+
+
-
The inhibitory receptor CD94/NKG2A recognizes HLA-E. However, a
cell synthesizing only HLA-E is killed because HLA-E must bind the
leader sequence from a class I molecule to get to the surface. Expression
of HLA-C with HLA-E provides the necessary leader sequence.
Antibodies to HLA-E or to the CD94 disrupt the interactions with the
inhibitory receptor and so killing takes place. Antibodies to HLA-C do
not disrupt the inhibitory signal since only the leader peptide, which is
acquired intracellularly, from HLA-C is required.
Note that the F1 expresses the MHC proteins of both parental strains
on its cells
Note that the F1 expresses the MHC proteins of both parental strains
on its cells
For class II there will be “heterozygote complementation”
Syngenic
- genetically identical
members of the same species
Congenic - individuals that differ
genetically only at a single genetic
locus or region (coisogenic)
Allogenic
- individuals of the
same species that differ genetically
Multiple different inhibitory and activating
receptors are being identified on NK cells.
Examples are:
The activating receptor NKG2D recognizes MICA and
MICB, MHC-1 proteins that are upregulated in
stressed cells and overexpressed by epithelial tumors.
The inhibitory receptor CD94/NKG2A recognizes
HLA-E (human) and Qa-1 (mice). These selectively
bind peptides derived from the leader sequence of
MHC-1 heavy chains. Thus proper expression of
HLA-E or Qa-1 is an indictor of normal expression of
MHC-1 molecules.