Transcript Overview of your immune system

Two types of T cells
• Killer T cells. Also called cytotoxic T lymphocytes
(CTLs)
– Coreceptor: CD8
– Recognize antigen bound by class I MHC molecules
– Can kill virally-infected cells
• Helper T cells (TH cells)
– Coreceptor: CD4
– Recognize antigen bound by class II MHC molecules
– Secrete cytokines that affect other immune system cells;
e.g., they activate macrophages and help B cells make
antibody
•
For completeness, but not for Bi1, there are also Regulatory T cells (Treg cells)
To understand T cells, we have to understand the
MHC proteins that present antigens to TCRs
Major Histocompatibility Complex (MHC)
• First discovered by tumor
immunologists working with inbred
mice.
• Grow tumors by passaging them in
mice. Tumors will only grow in the
genetic strain they came from.
Rejection of tumors results from
differences in normal cellular antigens
• The antigens causing tumor rejection are
polymorphic.
Polymorphic: genes different between individuals.
Each variant of a gene called an allele.
• Genes responsible for acceptance or rejection of
tumors defined as histocompatibility genes -encode cellular structures that are polymorphic
within species but immunogenic enough to evoke a
rejection reaction.
• Genetic region that determines graft rejection is
called major histocompatibility complex (MHC).
• The MHC encodes proteins (MHC class I
molecules) that determine the acceptance or
rejection of a graft.
• Differences between foreign and self are due to
genetic polymorphisms among different
histocompatibility alleles.
• Human MHC molecules are called “Human
Leukocyte Antigens” (HLA).
– Human MHC class I molecules are encoded in three loci:
HLA-A, HLA-B and HLA-C
– Different alleles of HLA are numbered:
e.g., HLA-A1, HLA-B27, HLA-C3
– Within the human population, there are hundreds of possible HLA-A
alleles, hundreds of HLA-B alleles, and hundreds of HLA-C alleles
Clicker question
MHC polymorphism is the result of:
1)
2)
3)
4)
Differential (alternative) RNA splicing
Gene recombination at the DNA level (as in
antibodies)
Mutation throughout the lifetime of an individual
Inherited genetic differences
Clicker question
1)
2)
3)
4)
5)
6)
There are hundreds of different of HLA-A
alleles, hundreds of HLA-B alleles, and hundreds
of HLA-C alleles. What is the maximum number
of different class I MHC proteins that any one
individual can express?
One
Three
Six
Twelve
Hundreds
Millions
Loci encoding human class I MHC
proteins are HLA-A, HLA-B, & HLA-C
Your class I MHC proteins:
HLA-A2, -A8, -B5, -B27, -C3, -C3
My class I MHC proteins:
HLA-A2, -A28, -B6, -B48, -C2, -C8
At least 100 alleles in human population at each
locus. MHC genes are most polymorphic genes
in genome of every species analyzed.
Clicker question
You need an organ transplant so you want to find a donor
who is most closely matched to your HLA haplotype.* In
the absence of knowing your HLA haplotype or anyone
else’s, from which of the following people is it safest for
you to obtain a donated organ?
1)
2)
3)
4)
5)
6)
Your mother
Your father
Your fraternal twin
One of your other siblings
Your roommate
Your Bi1 TA
* Your set of HLA proteins: e.g., HLA-A2, -A8, -B4, -B7, -C1, C8 plus your class II MHC molecules -- more about these later.
Your mother
HLA-A2, HLA-Aw68
HLA-B5, HLA-B27
HLA-Cw1, HLA-C4
Note 1: the scenario in which
you are a perfect match with
one of your siblings and
completely mismatched with
another is theoretically
possible, but unlikely.
Your father
HLA-A28, HLA-A44
HLA-B53, HLA-B55
HLA-Cw7, HLA-C18
You
HLA-A2, HLA-A28
HLA-B27, HLA-B53
HLA-C4, HLA-C18
Sibling 1
HLA-Aw68, HLA-A44
HLA-B5, HLA-B55
HLA-Cw1, HLA-Cw7
Note 2: Class I MHC
molecules are expressed on
all nucleated cells. Each cell
expresses all class I
molecules, not a subset.
Sibling 2
HLA-A2, HLA-A28
HLA-B27, HLA-B53
HLA-C4, HLA-C18
Clicker question
Why does a woman tolerate a fetus?
1)
2)
3)
4)
5)
6)
The fetus has the same MHC molecules as its
mother.
Half of the fetus’ MHC proteins are the same
as the mother’s -- this is enough to prevent
graft rejection.
The outermost layer of the placenta does not
express MHC molecules.
She only tolerates it for 9 months, then she
rejects it.
Tolerating a fetus is good practice for
tolerating a teenager later.
No one knows.
Clicker question
Why did the immune system evolve to reject
transplanted organs?
1)
2)
3)
4)
To prevent animals from exchanging grafts in the
wild.
To frustrate transplantation surgeons.
To force Bi1 students to learn about
histocompatibility and MHC molecules.
Because graft rejection is a by-product of an
essential immune function.
Zinkernagel & Doherty, 1974
Infect mouse with virus A.
Isolate cytotoxic T lymphocytes (CTLs or “killer”
T cells) from spleen of mouse X.
Look for killing of virally-infected target cells
derived from self (X) or non-self (Y) mouse.
Killing
+
-
CTL
X
X
X
Target
X
X
Y
Virus
A
B
A
See Bi1 website for link to Zinkernagel and Doherty’s 1996 Nobel prize for this experiment.
Clicker question
Which of the following scenarios
explains Zinkernagel and Doherty’s data?
1) T cells have two types of receptor; one for antigen
and the other for MHC. Both receptors must be
occupied to get killing.
2) T cells have one type of receptor, which recognizes
a complex between the MHC molecule and the antigen.
3) Both scenarios explain the data.
4) Neither scenario explains the data.
Antibodies recognize free and
cell-bound antigens independent
of MHC proteins
TCR recognizes a viral antigen and an
MHC molecule, perhaps in a complex.
One receptor, two receptors?
Now understood that
TCRs recognize
antigen in the form of a
peptide* bound to
an MHC protein.
The receptors on B cells (antibodies) are made in both membrane and
secreted forms.
The receptors on T cells (TCRs) exist only as membrane-bound proteins.
Viral proteins are
degraded into peptides
inside cells and presented
on class I MHC proteins
for recognition by
T cell receptors (TCRs) on
cytotoxic T lymphocytes
(CTLs or “killer” T cells).
* Peptide: A short fragment of a protein.
In general, a peptide is considered to be a
protein if it is ≥50 amino acid residues. The
peptides presented by class I MHC
molecules are 7-10 residues.
• Note that T cell mediated responses are
restricted to CELLS, whereas antibodies
can see soluble antigens (e.g., viruses).
T cells can’t kill viruses, can only kill virallyinfected cells.
• Viruses can mutate rapidly so can easily
destroy antibody epitope, then virus can’t
be neutralized. Mutated virus goes on to
infect cells, but infected cells can be killed
by T cells. Unlikely that virus can make all
peptide sequences different to prevent
binding to all MHC molecules.
Class I MHC proteins
Crystal structure of HLA-A2
• Peptide binding site identified
as groove between a1 and a2
domain helices; allele-specific
differences cluster in groove.
• Groove was occupied by
mixture of peptides although
cells from which protein was
purified were not expected to
be presenting antigen.
• Implies that MHC proteins
always presenting peptides -why don’t T cells recognize
MHC/self peptides and kill
uninfected cells?
Remember: Viral proteins
are degraded inside cells
and presented on
class I MHC proteins for
recognition by TCRs on
cytotoxic T lymphocytes
(CTLs or “killer” T cells).
• MHC molecules are (almost) always occupied with peptides (usually self
peptides, occasionally non-self peptides), so T cell has be able to distinguish.
• Auto-immune diseases result from T cells that mistake a harmless self peptide
for a dangerous non-self peptide.
• Graft rejection results from a cross-reaction in which non-self MHC plus
peptide Y (random self peptide) “looks like” self MHC plus peptide X (pathogenderived peptide).
The receptors on T cells (TCRs) exist only as membrane-bound proteins.
Variable residues
located within
peptide-binding
site create different
environments for
binding different
types of peptides
Allele-specific peptide binding motifs
Allele 1
Allele 2
Different class I MHC molecules bind to different types of peptides, but peptides
that bind to every allele are (almost) always 7-10 residues long and usually have a
hydrophobic C-terminus. Class I MHC-binding peptides can be predicted by
computational analysis of protein sequences. See link on reading/links for today’s
lecture on Bi1 website.
Janeway et al., The Immune System in Health and Disease; Garland Publishing
DR and Dw molecules are
class II MHC proteins.
Goldsby, Kindt, Osborne, Kuby. Immunology, 5th edition.
Rusty, the narcoleptic dog
<http://www.devilducky.com/media/8232/
Review: The cellular immune response evolved to deal
with viruses that mutate and hide out in cells
• Many viruses, including HIV, rapidly mutate so
that antibodies produced against one strain
don’t react with new strains.
• Another problem: once a virus enters a cell,
antibodies can’t access it, so it can make
thousands of copies of itself.
• The cellular immune response (T cell
mediated) can usually deal with both viral
mutations and intracellular viruses.
Comparison of antibody versus T cell epitopes on a model antigen
shows how the antibody-mediated (humoral) and cellular immune
responses are complementary
Discontinuous epitopes (adjacent in
3D space, but not in sequence) on
the surface of a protein are
recognized by antibodies.
Linear epitopes recognized by TCRs.
Note red epitope is in interior of
protein and only accessible after
unfolding and proteolytic degradation.
Easier for a viral protein to mutate to escape antibodies than to escape from T cells
Janeway et al. (2001) Immunobiology: The immune system in health and disease. Garland Publishing, 5th edition
Clicker question
At what level is the polymorphism of MHC
molecules a benefit?
A) An individual  has a variety of MHC
proteins to present various antigens.
B) A population  not wiped out by a single viral
infection.
C) Both.
Clicker question
Heterozygosity of MHC is advantageous because it
doubles the chances that a given antigen will be
presented.
How is MHC heterozygosity maintained in a
population?
A) Completely homozygous individuals are non-viable.
B) MHC molecules mutate throughout an individual’s lifetime.
C) Different cells express different MHC alleles, so
homozygous individuals become heterozygous.
D) Individuals prefer mates that express different MHC
alleles than theirs.
MHC and behavior
• Heterozygosity of MHC is advantageous
because it doubles the chances that a given
antigen will be presented.
• How is MHC heterozygosity maintained in a
population?
Answer: MHC affects mating choice
• Mice preferentially mate with mice that are MHC disparate.
• Female mice will spontaneously abort a fetus that is MHCsimilar if they smell urine from a male that is MHC disparate
(the Bruce effect).
• T shirt study suggests similar mechanism influences mate
choice in humans (link to this paper on Bi1 website).
• MHC-based dating service (see link on Bi1 website).
Clicker question
Smell is very important to me in choosing a
boyfriend/girlfriend.
1)
2)
True
False
MHC heterozygosity delays the progression
to AIDS in HIV-infected individuals
Heterozygous for MHC I and II
Homozygous for one MHC locus
Homozygous for two or three loci