PROFESSOR: All right.
So today, we're going to
talk about immunity again.
And so this movie up
on the screen here--
this is a cell.
You can see the outline of
the cells kind of around here.
That's the outline of the cell.
But what you can
see is that there
is something in the
cell moving around,
and that is an intracellular
bacteria called listeria.
And you can see it's
rocketing around in this cell.
It's having a total
party in this cell,
and what you'll see here is you
can often see the bacteria push
out from the cell.
So if you look here, one
is going to push right now.
See?
There it goes.
And it kind of runs into
the edge of the cell
and pushes out, and this
enables the bacteria
to spread from cell to
cell without actually going
into the extracellular space
surrounding the cells, OK?
So let's take a
hypothetical situation.
So listeria is a
foodborne illness.
It causes a nasty sort
of intestinal disease.
So Brett, do you want
these bacteria having
a party in your cells?
AUDIENCE: Unlikely.
PROFESSOR: Hell no.
OK, Malik, do you want
these bacteria having
a party in your cells?
Hell no.
Carmen, do you
want these bacteria
having a party in your cells?
AUDIENCE: Hell no.
PROFESSOR: Hell no!
Yes.
OK, so our body has to have
some way to sort of address
this type of an
illness, and the problem
is if you're thinking about what
we discussed on Wednesday, is--
all right.
So you're hosting
this party, right?
This is your cell.
So you have a host cell--
that's your cell-- and you
have an intracellular pathogen,
such as a bacteria or it
could also be a virus,
and they're essentially
using your generous host
cell to reproduce
itself to spread
to other cells of the body.
And so you don't want that,
but the problem is that--
I told you about B cells,
so remember B cells--
they have an antigen receptor.
It's initially on
their plasma membrane.
It can also be secreted,
and it's secreted
into the extracellular space.
The problem is that these
pathogens are inside the cell,
and there's a plasma
membrane separating them
from the antigen receptors that
you need to recognize them, OK?
So this presents an issue.
It's also the case for T
cells, because as you heard
on Wednesday, T cells only
have this membrane-bound form
of the receptor, and the antigen
recognition domains of all
of these are extracellular,
so there is really--
with just this system, there's
no way for your immune cells
to see in the cells.
So today, I want
to talk about how
is it that the immune
cells are able--
how our immune cells are
able to see within the cell
in order to address an infection
like this one, with listeria.
OK?
And the first part
of the answer is
that it involves a process
known as antigen presentation.
And antigen presentation
is the process
by which peptides, so short
sequences of amino acids,
are presented and displayed
on the surface of the cell
for the immune system--
for immune cells to see.
So here, peptides are
displayed on the cell surface
for immune cells to see them.
And in this specific case, it's
going to be for the T cells
to observe what's going
on inside the cell, OK?
So this mechanism
involves another molecule,
which I briefly introduced.
It's called the major
histocompatibility complex,
which is abbreviated MHC.
So when I referred to MHC
in Wednesday's lecture,
I was referring to this major
histocompatibility complex.
And there are two
classes of MHCs.
Thankfully, the first
one is known as class 1,
so class 1 MHC, and class
1 MHC looks like this.
Like many of the
immune receptors
that I've talked about,
it has a heavy chain,
which is this long
polypeptide light blue,
and it has a light
chain in purple.
So the MHC is composed of these
two separate polypeptides.
They're encoded by
different genes,
and then it assembles into
this structure shown here.
So this molecule
has two Ig domains,
and these are proximal
to the plasma membrane.
And this thing is all inserted
in the plasma membrane.
It's an integral
membrane protein.
And then distal to
the plasma membrane
is this structure
here, and if you
look at the crystal structure,
it's kind of like a sheet--
a beta sheet with
two alpha helices.
And altogether what it does
is it basically creates,
like, a little cup, OK?
So it's creating, like, a cup.
And what sits in this cup is a
peptide, so you get peptides,
and the peptides sort of sit
in that hand, if you will.
And some of the amino acids from
that peptide are sticking out
and they're sort of displayed
away from the MHC molecule.
So this is basically a hand
that holds peptides and displays
them on the outside
of the cell, right?
So the outside of
the cell here is up.
This would be the
exoplasm out here,
and it's displaying these
peptides for immune cells
like T cells to observe.
All right.
So class 1 MHC is a
class that's expressed
on all nucleated
cells in your body.
So that's all of
your nucleotide cells
are synthesizing
in a class 1 MHC,
and then it's sort of being
displayed on the surface.
And the peptides that are
held by this class 1 MHC--
the peptides here
are being derived
from a specific place in the
cell, which is the cytoplasm.
So the peptides are
from the cytoplasm,
so this is the source
of the peptides,
and I'll tell you how these
peptides are sort of loaded
on to this MHC molecule.
So the MHC molecule
is a membrane protein,
so it's translated on the
endoplasmic reticulum,
and its extracellular
domain is initially
present in the lumen of the ER.
And the peptides
are from proteins
that are present
in the cytoplasm,
and what happens
to these proteins--
and this occurs for
unfolded proteins,
but also for proteins that
might be ubiquitinated--
is that they're processed
by the proteasome, which
is this kind of a shredder-like
function for proteins,
and it cuts up the proteins into
little snippets, or peptides,
that can then be pumped
into the lumen of the ER
through this transporter, TAP.
So these peptides can
be taken and transported
into the lumen of
the ER, and that's
where they're loaded onto
the class 1 MHC molecule.
But the source peptides
is from proteins
that are in the cytoplasm.
They're processed
by the proteasome.
So then, once you have
a peptide-MHC complex,
it can then be trafficked
through the normal vesicle
trafficking pathway all the
way out to the plasma membrane
of the cell where now that
peptide will be displayed
for T cells to observe.
And so the peptides
here, they're
processed by the proteasome--
processed or cut
by the proteasome--
and then the type
of T cell that's
going to look at these
class 1 molecules--
they are known as seeds
CD8 positive T cells.
So this is the first
class of MHC molecule.
Because there is a
class 1, that means
there also must be a
class 2, which there is.
And so class 2 MHCs are
fundamentally different in all
of these properties.
The function shared
by these MHC molecules
is they both display peptides
on the surface of the cell.
So MHC molecules
do display peptides
on the surface, which is
known as antigen presentation.
But other than that, MHC
class 2 is pretty different.
You see the structure
of MHC class 2
is very similar to
that of class 1,
but you see that
rather than having
a heavy and a light
chain, here there
are two chains that are
roughly of equal size.
And so these are encoded
by different genes
than the class 1 molecule, and
they encode different proteins.
But the overall structural
similarity is very similar,
so there are two
Ig domains, they're
proximal to the plasma
membrane, and then there's
this structure at the very
end of the MHC molecule,
which has this
groove in it which
can hold a peptide
that would be displayed
on the surface of the cell.
And there, you see the groove
and you see the peptide
that is present in it.
All right, so one big difference
between class 1 and class 2
is that class 2 is expressed
on a much more restricted set
of cells.
So class 2 MHCs are expressed
specifically on specialized
cells known as
antigen-presenting cells,
and these antigen presenting
cells include cells like B
cells, which are the ones
that I'll focus on, but also
phagocytic that can phagocytose
foreign substances--
phagocytic cells-- and
there's another cell type
called the dendritic
cell, which is also
an antigen-presenting cell.
I'm going to focus
on the B cells.
So class 1 is
expressed everywhere.
Class 2 is really expressed
on these professional
antigen-presenting cells.
And the way that the peptides--
the source of the peptides
and the way they're generated
is also very different.
So peptides for class 2 come
from the extracellular space,
and they are processed
by lysosomal proteases.
And so I'll show you how
that looks in cartoon form.
So for MHC class
2, the peptides are
from the extracellular space.
And so we've talked
about ways that cells
can take in material.
One way is through
endocytosis, right?
So if this is my
antigen, the antigen
could be endocytosed
by the cell,
and now it's in a vesicle
that's present in the cell.
And so if you
endocytose this protein,
then it's now in a vesicle,
and one compartment
that it can go to
is the lysosome,
where are these there are
these lysosomal proteases they
can then chop up this
protein into little snippets,
or peptides.
And so MHC class 2,
again, is translated
at the end of
endoplasmic reticulum,
like all plasma
membrane proteins.
But in the
endoplasmic reticulum,
you see the peptide
groove is blocked such
that peptides derived
from the cytoplasm
can't interact with
class 2, but then
is trafficked to a unique
compartment which can combine
with the compartment that has
the peptides that originated
from outside the cell.
And then those can get loaded
onto this class 2 MHC molecule,
and then this can be
recognized by T cells.
But in this case, it is a--
oh, I endocytosed my chalk.
I need to get it back.
Here.
So in this case, it's not a CD8
T cell that's recognizing it,
but a CD4 positive T cell.
OK, so let me briefly review
what I just went through,
and review the differences
between class 1 and class 2.
So class 1 MHC is expressed
on all nucleated cells,
whereas class 2 is
much more restricted,
being expressed specifically
on antigen-presenting cells.
The T cells that recognize
these two classes are different.
Class 1's recognized by
CD8 positive T cells.
Class 2 is recognized
by CD4 positive T cells.
And the source of the antigen
is different in these two cases.
The source of the antigen
for class 1 is the cytoplasm.
For class 2, it's the
extracellular space.
So the different MHCs are
sampling different sort
of pools of proteins.
And where the
peptide is loaded is
distinct between
these two, which
allows these distinct
classes to basically
discriminate between the
sources of the peptides
that they're loading.
So for class 1,
that's in the ER.
For class 2, it arises
from a vesicle compartment
that results from
endocytosis of an antigen
from outside the cell.
All right.
Now, the type of molecule
that recognizes this MHC
peptide complex is the T cell
receptor, which I briefly
outlined on Wednesday,
but now we're
going to talk about it
in much more detail.
So the T cell receptor, or TCR--
and I talked about its structure
which is shown up on the slide,
but I'll just draw
more simply here.
If this is the plasma membrane,
this is the cytoplasm,
and this is the
exoplasm facing down,
then this T cell
receptor has two chains.
One is called the alpha
chain, and the second
is called the beta chain.
And each is comprised
of two Ig domains,
which you see up there.
So the T cell receptor
here is in pink.
You can see an Ig domain
there on one strand--
Ig domain there.
And you have another two Ig
domains on the other subunit,
and this receptor,
the T cell receptor,
recognizes antigens through its
variable domain, which is here.
And it's binding basically
to the end of this receptor,
so this is a sort of ribbon
diagram of a structure for a T
cell receptor.
The plasma membrane
would be up here.
This is the end of
the T cell receptor.
And MHC is in green, and
it's holding a peptide here
in yellow.
And you can see how the TCR is
sort of interacting or docking
to this MHC-peptide complex.
So for the T cell receptor
to interact and bind to MHC,
you have to have a
T cell receptor that
recognizes the
specific conformation
of the peptide that is
being sort of extended away
from the cell.
So let's say this is
my T cell receptor,
and I'm going around and
searching for cells that
might want to look at this.
Then if I had a T cell
receptor that was like this,
it's not going to
be able to stick
to this MHC-peptide complex.
However, if I had a
T cell receptor that
had the right
conformation, because there
are different types
of T cell receptors,
it might be able to dock on
and stick to the peptide,
and then the T cell is now stuck
to the peptide-MHC complex, OK?
So there are different
T cell receptors.
There's a diversity
of T cell receptors,
and they're able to discriminate
between different peptides
loaded onto MHC.
OK, so now, we have to think
about where this diversity of T
cell receptors comes from.
There's a diversity of
TCRs, and lucky for you,
the mechanism that generates
the diversity of TCRs
is the same that generates
diversity for antibodies.
Now, Georgia asked a really
good and really important
question at the end of
lecture on Wednesday,
which is-- she asked if
this sort of rearrangement
of gene segments in the
variable domain of the antibody
was due to splicing
or recombination
at the genomic locus.
And the answer is that
it's recombination
at the genomic locus, and
that's a very important point.
So here's a diagram for
the beta chain of the TCR.
You can see that like
the B cell receptor,
there's a gene rearrangement
in the genomic DNA that
brings V, D, and J
segments together to make
the variable chain of
the T cell receptor.
So like the B cell receptor,
there is a gene rearrangement,
also known as VDJ
recombination, and this is not
splicing of the transcript.
This is in the genomic DNA--
a very important point,
because by having
this happen in the
genomic DNA, it
creates an irreversible
change in that genomic DNA
such that all
subsequent cells that
are derived from that
original B or T cell
are going to express the
identical B or T cell receptor.
So it's not splicing,
but it's a real sort
of irreversible change
to the genomic DNA.
So you have a diversity of T
cell receptors, but the T cell
receptor is not
the only thing that
enables the T cell to
interact with whatever cell
is presenting the antigen. There
are these other co-receptors
which are important.
So there are co-receptors
on the T cell--
this is on the T cell--
and the co-receptors
are CD4 and CD8,
and they're expressed on
different subsets of T cells.
And these co-receptors--
because it's not sufficient
for just the T cell
receptor to interact
with a specific peptide,
it also requires
this co-receptor in order
to get an immune response.
So the logic is
that if the T cell
receptor and the co-receptor
both bind to the MHC,
then you get a particular type
of response, so you need both.
And CD4 cells recognize
the class 2 of MHC.
CD8 recognizes class 1 MHC.
So you have these two
different subsets of T cells
and they recognize these
distinct MHC complexes.
So my question for you is what
should these CD8 positive T
cells do?
To help with that,
you might want
to look at where the
peptides are coming from that
are presented on the class 1
MHCs, which are going to be
presenting specifically to CD8.
So what should these do?
What does it mean if you have a
class 1 MHC molecule containing
a peptide that looks foreign?
Well, where do the
peptides come from?
What's that, Patricia?
Patricia is right.
They're coming from the cytosol.
So if you have foreign elements
coming from the cytosol,
what might that
mean for that cell?
Good, bad, irrelevant?
What's that?
AUDIENCE: [INAUDIBLE]
PROFESSOR: What's that?
OK, Brett's saying it
needs to be dealt with,
and I totally agree.
Here's one scenario--
would be the scenario
I showed you in the
beginning of class
where you have some sort
of intracellular parasite
that is basically using the host
cell for its own evil purposes
to produce more viruses
or more bacteria.
So if the immune cell has
some sort of indication
that this is going wrong,
another example is in cancer,
because if you have oncogenic
mutations in certain genes,
then those could be
recognized as foreign.
And so an appropriate
response might
be to do something to
that cell that would limit
the expansion of the tumor.
Or in the case of an
intracellular parasite,
you really need to
terminate the cell
so that you stem the tide
of viruses that are going
to be produced by that cell.
So the response
should be to kill.
So it was CD8 positive.
If you have a CD8
positive T cell,
it indicates there's something
wrong inside that cell,
and the response
should be to kill it.
And these CD8 positive
T cells are known
as killer or cytotoxic T cells.
So what happens if a CD8
positive T cell recognizes
a MHC class 1 peptide
complex, then it
releases materials from inside
it that perforate that cell
and lead it to
undergo cell death.
So it's a way of
limiting an infection
by killing the cells that
the virus or pathogen is
using to reproduce itself.
OK, what about CD4 positive?
What should be the response
of a CD4 positive T cell?
Should it also kill?
Should be like the T-1000?
No one gets my
cultural references.
Yeah.
Should it be the Terminator 2?
No.
Yes or no?
Who thinks it should terminate?
OK.
Steven, can you
tell us your logic?
Why should it not terminate?
AUDIENCE: Because
it's a [INAUDIBLE] B
cell from the same [INAUDIBLE].
PROFESSOR: What are
the MHC class 2 cells?
AUDIENCE: Like, a B
cell or [INAUDIBLE]..
PROFESSOR: Yeah.
It's not only a B
cell, it's a B cell
that recognizes
the foreign agent
that you're infected with.
Yeah, Brett?
AUDIENCE: So those B cells
are antigen presenting cells.
They have the information
about what is bad
or what is wrong in
probably other cells?
So like, oh, hey, we
have this information.
You should go and mobilize.
PROFESSOR: They're
binding something
that it recognizes as foreign,
internalizing it, and then
presenting bits of
that foreign element
on the outside of itself.
AUDIENCE: Shoots the messenger.
PROFESSOR: What's that?
It's shooting the
messenger, exactly.
Yeah.
So it would be an extremely
bad idea for the CD4 positive T
cell to kill what's
presenting the antigen,
because you would kill the
exact cell that you would need
to fight that antigen, right?
Here you have a B cell.
It would be a B cell that's
producing an antibody that
actually can produce
antibodies that
might be able to neutralize
that foreign invader,
and so you don't
want to kill it.
You want to help it or
enhance the B cell function.
And so these CD4 positive cells
are known as helper T cells,
and they enhance B cell function
in a number of different ways.
Oh, I should point out
where this happens.
So this sort of interaction
between B and T cells
happens in the lymph node,
because in the lymph node,
you have antigen-presenting
cells, or even
soluble antigens, coming
into these lymph nodes.
And you also have B
and T cells, and this
is kind of like the
B and T cell hangout
to get sort of, like,
interactions between these two
distinct immune cell types.
And when you get
sort of a B cell
that presents an antigen
that's recognized by a T cell,
then the T cell enhances
B cell function,
and it does so in a
number of different ways.
The first way that it induces
a response in the B cell,
known as affinity maturation.
And this affinity maturation
results from a hypermutation
of the variable domain
of the antibody such
that you get even more
diversity, and such
that a B cell can be selected
that even has a tighter binding
to the antigen.
So for affinity
maturation, this is
responsible for the
transition in binding
from a more weak binding
to a tighter binding,
which I talked about
as being a difference
between the primary infection
and the secondary sort
of immune response, OK?
So the antibodies get better
because of this B and T cell
interaction and this
affinity maturation process.
One other thing that happens
is that the B cells can produce
different classes or
isotypes of antibodies,
and this is known as
isotype switching.
And so this is, again,
the genomic locus
for the heavy chain
of an immunoglobulin.
You see, here's the
VDJ segment, so it's
undergone VDJ
recombination, and then
what you see are these
different blue regions here.
Each of these are exons that
encode a different isotope
for the antibody.
So the first one
is mu, and so that
produces IgM when that's the
one that's proximal to VDJ.
So if you have IgM, that's the
initial state of the antibody,
and that's initially
membrane bound
and serves as the
B cell receptor.
But each of these
different constant domains,
even though they're not
undergoing variation,
they have different
effector functions
and can do different
things for the body.
So for example, if you
had isotype switching
and you had a
recombination event that
brought this gamma 2
segment together with VDJ,
that would produce the
isotype which is known as IgG,
and IgG is a highly secreted
form of the antibody that
is highly effective for
bacterial infections
because it's secreted
in the blood,
and it's able to neutralize
bacteria and limit
the infection that way.
But there are other
possibilities,
because you have all of these
different possibilities.
And so you could get VDJ
together with this alpha,
and that would produce
an isotype known as IgA.
And IgA promotes
mucosal immunity
because it's able to pass
through the epithelial linings.
In addition, IgE is
another type of antibody,
and the constant domains are
constant for each of isotypes,
but they recruit different
effector functions.
So IgG would be hitting
bacteria by promoting
phagocytosis of those bacteria.
IgE, in contrast, is especially
good at dealing with worms,
right?
So if you have an
intracellular--
or not intracellular, but like,
an intestinal worm or something
like that, then IgE--
its effector functions are
better at dealing with that.
So this process of
isotype switching sort of
allows the immune system
to adapt to tackle
a particular type of pathogen.
All right.
The last way in which T
cells enhance this function
is by promoting the
differentiation of B cells
into different types of B cells.
One of those types of B cells
is known as a memory B cell,
and the memory B
cell is a B cell
that can last in the
body for decades,
even if the antigen
is not present.
So this mediates sort of the
memory of the immune system.
And so just to summarize
what I just told you,
if you have a B cell and it
recognizes an antigen, which
could be a protein, it would
internalize that protein
via endocytosis
and then process it
so that it can display
peptides from that antigen
on its surface.
And if that's
recognized by a T cell,
then that leads to an
interaction between the T and B
cell that will lead to these
different things happening,
such as affinity maturation,
isotype switching,
so the red here would be
a different constant chain
on this same variable chain.
So the variable
chain doesn't change
with the isotype switching,
so it's still always
able to recognize that antigen--
it's just recruiting
different effector functions.
And you can also get
differentiation of B cells
into plasma cells, which really
secrete a ton of antibody,
and therefore help the
body fight infection.
Now this is important because
for a vaccine to be effective,
you need to engage this
T cell response such
that you have all of
these things happening.
So all of these
things need to happen
for an effective vaccine.
So for an effective
vaccine, you can't just
activate the humoral side
of the immune system.
You have to activate
both the humoral
and the cell-mediated sides
such that they interact in order
to enhance the immune response.
All right.
Now I'm going to move on
and talk about a big problem
that the immune
system has, which
is that it needs to somehow
be able to discriminate
between self and foreign, right?
And so if you have your
immune system recognizing
an antigen that is
natively part of your body,
that results in an
autoimmune disease.
So there's a balance
in the immune system
between tolerating
antigens or attacking them,
and if it's attacking a native
antigen, then it's autoimmune.
And this is a huge
problem because,
if you think about it, because
we've talked about the B cell
receptor, the antibody, and
the T cell receptor, right?
Our bodies are generating
tens of millions
of these receptors that
are diverse and can
recognize different molecules.
So our body is generating
tens of millions
of antigen receptors, and
it does this constitutively,
so that means that it's
just doing it automatically.
You don't even need to be
infected for this to happen.
This is just part of the
development of B and T cells.
OK, so it's constitutive,
doesn't require infection--
constitutive.
In addition, it's
totally random.
Your body could generate any
sort of combination of V, Ds,
and Js, and it could
mutate in a certain way
that it's likely that at some
point during your lifetime
you're going to generate
a receptor that recognizes
a native protein in your body.
So it's totally random--
at least what the sort of
rearrangement of VDJ gives.
That process is
constitutive and random.
So I just want to point
out several diseases that
are caused by autoimmunity,
and I've distinguished them
based on whether
the disease involves
the generation of antibodies
that recognize self or T
cells that recognize self.
So for antibodies, there's a
disease, myasthenia gravis,
which an individual's--
individuals generate
an antibody against a receptor
for a neurotransmitter,
acetylcholine.
And acetylcholine is
the neurotransmitter
which is predominantly involved
in sending signals from a motor
neuron to a muscle,
and therefore
antibodies that
inhibit this receptor
result in muscle weakness.
Now self antibodies can
also result in diabetes,
and individuals can
develop antibodies
that recognize and inhibit
the insulin receptor,
and this leads to insulin
resistance and diabetes
mellitus.
Some examples of T
cell mediated diseases
are-- if you recall back in
the beginning of the month,
when we talked about electrical
signaling in neurons,
I told you about
the myelin sheath
and how this increases
the speed of the action
potential along that axon.
And if T cells attack
the myelin sheath,
then it disrupts this process
of electrical signaling,
and that results in a
devastating disease,
which is multiple sclerosis.
Autoimmune disease involving T
cells also involves diabetes,
and if T cells
attack and destroy
the islet cells of the
pancreas, this also
disrupts the body's
ability to produce insulin,
and that results
in type 1 diabetes.
So I'm sure many
of you know people
with these types of diseases,
and they're obviously
of significant impact
both in this country
and around the world.
So the problem for the cells in
our body and the immune system
is that the immune system
has to have some sort of way
to distinguish between
self and foreign.
So how is it that the
immune system does this?
And also, it has to
have different responses
to self-recognition versus
foreign recognition.
So what should the
immune system's response
be if there is a
self recognition?
What should it do
to the cells that
recognizes a native protein?
Rachel?
AUDIENCE: [INAUDIBLE]
PROFESSOR: It could
delete that cell.
What Rachel said is you
should get rid of it.
And so one way to think
about this process
is there's a bit of a Darwinian
natural selection going on
in the body, and if there
is a self recognition,
then there should be a negative
selection against that cell,
so there should be
negative selection.
This cell should be more
unfit, whereas if it's
obviously foreign, then there
should be positive selection.
This B cell should be more fit.
And what Rachel
suggested is to get rid
of the cell, which is a great
idea, because if you kill off
the cell then you won't generate
any more cells that have
that recognition against self.
So negative selection is
mediated by apoptosis and cell
death.
And positive selection could be
both the activation of the cell
and also its proliferation.
As you see up on the slide
there, that orange cell--
if it was recognizing a foreign
antigen, would get activated
and it would undergo a
monoclonal expansion.
All the cells resulting
from that expansion
would express the same antibody
and therefore recognize
that antigen, so
this would result
in cell division or expansion
of that population of cell.
So now we know what to do
with self versus foreign,
but how is it that
we distinguish
between self and foreign?
So how does the immune system
distinguish self from foreign?
And there are several
mechanisms to do this.
The first is that the organs--
the lymphoid organs-- where
are these B and T cells
mature and undergo these
genomic rearrangements
are largely protected
from foreign agents.
So there are basically
only self antigens
in the generative
lymphoid organs.
These are the lymphoid
organs were B and T
cells are being generated.
So the generative
lymphoid organs
would be the bone
marrow for B cells
and the thymus for T cells.
Therefore, if a B or T cell--
if its receptor
engages with something
very tightly during
its development,
that's a signal for
the immune system
to delete and kill
off that cell.
So if you get self
recognition here,
you get apoptosis and
deletion of that cell.
The second way that the
body is able to distinguish
is that it responds to
antigens specifically
when there is an
innate immune response,
or if it responds
better when there
is an innate immune response.
So you can think of it like a
coincidence detector, right?
If you have an immune cell
and it recognizes an antigen,
and there's also an
innate immune response,
that's a strong indication
that this is foreign.
So this would indicate
"foreign" to the immune system.
If there is antigen
only and the body is not
mounting an innate
immune response,
it's much more likely
that this will generate
a robust immune response, and
this is the immune system's
signal that this
is a self antigen.
This is also important
for vaccine development
because in most
vaccines, in addition
to having some antigen that's
a part of the infectious agent,
there's also something called
an adjuvant, which is basically
something that activates
the innate immune system.
So the adjuvant activates
the innate immune response,
and that's important
because if you just
had the vaccine with
just the antigen,
there wouldn't be nearly
as robust a response.
So you need both to activate
the adaptive immune system,
but also the innate immune
system to really get
a robust response.
So I want to end by talking
about this year's Nobel Prize
work, and it involves
another mechanism that
basically prevents
autoimmunity and downregulates
the activity of these
T cells, and that
involves another type of-- we've
only talked about activating
receptors on the T cell, right?
The T cell receptor, CD4, CD8--
they're activating receptors
for the T cell receptor,
but there are also
inhibitory receptors that
are on the surface of T cells.
So inhibitory-- we'll
just call them receptors.
One is called CTLA4 and
another is called PD1.
Their names are not terribly
important, but what they do
is they keep the
immune system in check.
And we've talked a
lot about signaling
and how signaling
gets activated,
and often a step in signaling
is once you get the signal sent,
and it's been sent, there
is, like, a negative feedback
that then turns
off the signal such
that there's signal termination.
So you often have some
type of signal termination.
That way, you don't have just
a constitutive activation
of the signal,
which in this case
would be sort of inflammation
and an immune response,
and one or both of
these is involved
in sort of keeping the
immune system in check
and stopping it after you
get that initial reaction.
Now, the reason
this is so important
and why James Allison
and Tasuku Honjo won
the Nobel Prize is
they had the idea
to use this as a
therapy for cancer.
And it turns out that
some cancer cells
can express the ligand for
these inhibitory receptors
such that they can avoid the
immune system from recognizing
the tumor.
So this would be one case where
the tumor cell is expressing
the ligand for PD1, and that
inhibits the function of this T
cell receptor so that it
doesn't kill the tumor cell,
and that leads to the
expansion of the tumor
so the tumor can expand
in an unchecked way.
And what James Allison and
Tasuku Honjo determined
is that if you block
that inhibitory receptor,
then you sort of uncheck the
response of the immune system
such that these
immune cells are now
able to recognize the
tumor cells and kill them.
So by sort of blocking
the inhibitor,
you now have T cells-- these are
CD8 positive T cells that are
killer cells--
they will now recognize these
T cells and kill them off.
So there's what's known
as an inhibitor blockade
because you're
blocking the inhibitor,
and these inhibitors are
antibodies that recognize
these inhibitory receptors, and
they're now being used to treat
some forms of advanced cancer.
And so this is something
that the cancer
field and immunology fields
are both really excited about.
What might be one complication
with this type of treatment?
If you get rid of the
inhibitory receptors,
what might be a consequence?
Yeah, Steven?
AUDIENCE: Then you could
recognize other self cells that
inhibited [INAUDIBLE].
PROFESSOR: Yeah, you
get autoimmunity.
That's exactly right.
So one of the downsides
of this is that--
one of the side effects is
that you can have patients
with an autoimmune reaction.
So it's not the magic
bullet, but it's
a step in the right direction.
All right, we'll
see you next week.
