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- [Narrator] We are the
paradoxical ape, bipedal,
naked, large brain, long
the master of fire, tools,
and language, but still trying
to understand ourselves,
aware that death is inevitable,
yet filled with optimism.
We grow up slowly, we hand down knowledge,
we empathize and deceive,
we shape the future from
our shared understanding
of the past.
CARTA brings together experts
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we are and how we got here.
An exploration made possible
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(upbeat music)
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- Hi, thanks for coming to
listen to our talks today.
My name is Susan Kaech
and I'm Director of the NOMIS Center
for Immunobiology and
Microbial Pathogenesis
at the Salk Institute and
I wanna talk to you today
about something that's very relevant,
very forefront to our lives,
which is how does our
immune system remember?
How does our immune system
develop long-lived immunity
to pathogens that infect us
and cause obviously
severe illness and death
as what we're facing today
with the COVID-19 pandemic.
This is a photo that you might
remember yourself personally
having been vaccinated
with polio in the day
that the polio vaccine was
declared safe and effective
became something celebrated
and revered across the globe
because it meant that
children would be saved
and people would be saved
from this devastating illness.
Now being at the Salk Institute,
which was founded essentially
on the basis of the principle
of longterm immunity,
and normally we would be
sitting in the Salk auditorium
for the CARTA symposia, it reminds us,
cemented in some ways, if you will,
in our understanding the foundations
of how our immune system operates.
And what I wanna talk to you about today
is the basis of vaccination, why it works,
and how does our immune system develop
this long-lived immunity
to remember pathogens
that we've experienced prior.
Now, all living organisms
have some form of immunity
and immune defense, and
these immune systems,
these immune responses, this
form of immunity is shaped
on fundamental traits, cardinal traits.
Now every animal has
the ability to recognize
and sense pathogens in the environment
and to incorporate that diversity
of the different types of pathogens
that the animal can sense,
and plants of course as well,
can sense this diversity must be immense.
To have the ability to
sense and recognize numerous
and many different types of
pathogens in our environment.
And so this diversity is one
we call the cardinal traits,
but specificity is also essential
and the ability to recognize
the pathogen from self.
The self/non-self
recognition is also essential
so that our immune systems
are appropriately defending
against the right types of
organisms and not attacking self,
which obviously is
something that breaks down
in the form of other immune disease.
So having this specificity,
this non-self/self recognition
is important for the proper
control of our immune system
and also specificity for being
able to precisely recognize
the pathogens that cause
damage from the microbes
that actually are beneficial.
Such as those are in our
microbiome, our commensals,
those types of beneficial microbes
for which we wanna develop tolerance to
and not have immune responses against.
So specificity, diversity
are two of the traits.
And the third trait that's
actually more unique
to our own immune systems is this ability
to develop long-lived immunity.
The ability of our immune
systems to remember.
We often think of memory
as part of our brain
and what our neurons do,
but our immune system can also remember.
And just instilling this
long-lived immunological memory
is another cardinal trait
of our immune system.
So you can think about when
we're exposed to a pathogen
and for the first time,
our immune systems have
two fundamental jobs
that they need to do.
Job number one is to fight
the present infection.
We need to clean up the house.
We need to tame the fires.
We need to eradicate that pathogen.
And so finding that present infection
is obviously essential for health.
Our second job though, that
our immune system has to do,
is to control the future infection.
How do we protect ourselves
against that same pathogen
should we encounter it again?
And the chances that
you've encountered it once
are very high that you're
going to encounter it again.
So how do we develop this
ability to protect ourselves
from the present infection
as well as enable our bodies
to develop immunity and
defenses to future infection?
Now, this has been observed in history
for thousands of years.
The first written observations
of longterm immunity
came from the Greek historian, Thucydides,
in the early 400 BCs during
the Plague of Athens,
where he noted that
individuals who had recovered
from the plague, they were
able to care for the sick
and they would not
experience the illness again.
And he noted by saying that the same man
that was never attacked
twice, at least fatally.
So it was observed that
these people that recover
from the infection could
actually not experience
the same severe illness or death again.
And so that was one of the
first written observations
of protective immunity.
But what was probably
the most evident form
of experimentally was when
the use of vaccination
was first indoctrinated into our society.
And this was the famous experiment.
It was really an experiment
by Edward Jenner in 1796
where he had noticed that
milkmaids who developed cowpox
and others had noted that
they were more resistant
to developing smallpox.
So it was observed again,
that these milkmaids
were immune to getting smallpox.
And because he saw that
the pustules of the cowpox
that these milkmaids would get,
the pustules look very
similar to the pustules
that were observed on people
who were infected with smallpox.
He actually had the intuition that perhaps
there was a common or a
similar agent that was causing
these diseases because of the similarity
in the manifestation of the disease
and these pox blisters that
would form on the skin.
And so he thought with
this knowledge that perhaps
that he could give
somebody the cowpox virus
which to what these milkmaids
were having happened just
by their exposure to the cows,
that if he were able to
give another person cowpox,
that that might induce a form of immunity
to the cowpox virus that
would be cross-reactive,
be cross protective to the
agent that caused smallpox.
And this was before we understood viruses
and he was able to show by
immunizing then James Phipps
with some of the fluid
from a cowpox blister.
He saw that when he did that,
he put it on the skin of the little boy
that a blister did form.
And then he waited a couple months
and did the experiment that of
course cannot be done today.
He then inoculated this little boy
with the scab of a blister
from someone who had smallpox
and tested whether or not
this child got the disease
and no disease formed in this child.
So this was the first
evidence of vaccination,
the first experimental
evidence that one could use.
And in this case, what
was also very interesting,
is that it used a very
similar type of a virus,
not the actual virus, but a
very similar type of virus,
enables you to get
cross-protective immunity
to the smallpox virus.
And so over the next hundreds of years,
then obviously trying to understand
what was the cause of this immunity.
What was the molecular and cellular basis
of this immunity created
the field of immunology.
In the late 1800s, Dr.
Kitasato and Emil von Berhing
were some of the first to
really start to identify
and I guess provide evidence
that there were products
in our circulation that could
provide this type of immunity.
And these were experiments
that they had been doing
by working with diptheria
where they would immunize
with the diptheria into animals.
And then they would wait and the animals
that were able to recover
from that diptheria infection
or the toxin at that time,
they could then transfer
the serum from those animals
into animals who had not been exposed
to the diptheria toxin.
And then they were able to find
that that transfer of serum
that was able to provide
immunity to those animals
that they were then
challenged with diptheria.
So there was something
protective in the blood
and serum of these animals
that were previously exposed
to the diptheria toxin
that when they were able
to transfer this serum was
able to protect those animals
from developing disease and death.
And they also did this for
tetanus around the same time.
And then moving forward
a few hundred years,
what we were able to then
discover was that the basis
of this protection was the molecule,
which is an antibody which
is shown here on the slide,
which is a beautifully
shaped Y-shaped antibody
that has these variable
regions for detecting
and binding very specifically
to the parts of the pathogen
that the antibodies are
being formed against.
And this is what forms,
what we refer to as the variable regions,
which is where that diversity comes from.
And these regions of the
antibody can be different
for every different type of a pathogen
or a non-self protein that our
immune system can recognize.
This diversity is encountered
because ends of these
antibodies can be different
for different antibodies.
And so this creates the diversity
but also the specificity
because these are able
to specifically recognize
these foreign antigens.
Now these antibodies are produced
by certain types of
immune cells in our body,
which are B cells, also
called plasma cells.
And these cells are
essential for providing us
with this humoral immunity
that antibodies provide.
Now, antibodies have many different ways
in which they can protect
but one of the ways
that is most notable is that
these antibodies combine
to regions of viruses
such as in SARS-CoV-2,
something that we're
learning a lot about today,
combine to the proteins on
the outside of the virus.
And that these antibodies
can then, by binding there,
can inhibit that virus from binding
to the cellular host proteins
on the surface of our cells,
such as the ACE2 protein,
the receptor for SARS-CoV-2.
And this can the neutralize that virus
from being able to infect those cells.
So these are some of the
ways in which antibodies
can be quite protective.
And this is how passive
immunity was actually used
because it was able to
provide the antibodies
that could then coat the pathogens
and prevent them from protecting.
Now, passive immunity is something
that naturally occurs all the time
as we breastfeed our children.
And the passage of antibodies
from the mom to the child
is something that happens all the time
and is a very important
process for early health
in our babies and young children.
So this type of passive
immune therapy of serum
was then widely adopted
after these early discoveries
of transferring those
serum from recovered people
who had been exposed to an
infectious agent to people
who were succumbing and
having severe disease
to prevent death to those infections.
And also it started to be
adopted with animals serum.
Animals would be immunized
to some of these toxins
and the antibodies from these
animals will then be used
to treat people who were also suffering
from various infections.
And so this form of passive immune therapy
was used widely in the early 1900s.
It was used for the 1918 Spanish flu.
It was used for measles.
It's been used, even more recently,
with the outbreaks of
Ebola and the past SARS
and even the current SARS pandemic.
Some form of passive immune
therapy is being used.
But what's important is that to realize
that this is not a vaccine.
This is a treatment because
this does not provide
long-lived immunity.
The transfer of these antibodies
that the therapy lasts only
for as long as these
proteins were persistent
in circulation of the recipient's body.
And so they usually last for a few weeks
unless you keep giving delivered.
So it's not the way in which
we induce long-lived immunity.
But the reason why I
wanted to bring this up
was because it's important
'cause this is how we
first started to understand
what was the basis of immunity.
And so passive immune
therapy gave us this evidence
that we do have circulating
products and cells
in our body that can provide immunity.
And so what are those cells
and then how do they form?
And that's something that my
lab has been interested in
working on for many decades now.
You can think about the
cells that give rise
to this long-lived immunological memory
in basically two types of cells.
There's the memory B cells
that we already talked about,
which produce the antibodies
and the long-lived plasma cells that just,
they continuously pump out antibodies
once they've been created,
because they've been exposed
to the pathogen or to the toxin.
Once they've been created,
they will continue to produce
antibodies constitutively.
But you also have these
long-lived memory B cells
that remember that pathogen
that they were first generated against
and that they can go on to
persist for long periods of time
as well to remount a secondary
response when it comes.
And we also have memory T cells
and these are the cell
types that I work on.
We have two different classes of T cells.
We have CD4 helper cells,
we have CD8 killer cells
and these are very important T cells
to help us fight against
different types of infections.
CD8 T cells are very important
for fighting viral infections
and CD4 and CD8 combined are important
for many other types of pathogens
that are infected with us.
But the important thing to know
is that the basis of
generating immunological memory
consist of these main cell types:
our memory T cells and our memory B cells.
And that inducing these cells
then is the ultimate goal
of what a protective vaccine would do
or using immunotherapies to
modulate the functionality
and the formation of these
cells during an immune response.
So how do these cells form?
We know how they form by
studying many models of infection
and also profiling now
the immune responses
in humans over different
types of viral infections
or in vaccines such as
yellow fever vaccine
and smallpox vaccine.
These have been well
characterized in humans now,
but the general characteristics
of an immune response
consists of three phases.
There's the first phase
when the infection initiates
and the virus, for instance,
and the viral infection starts to expand.
And this we refer to
as the expansion phase.
And while we have very
few viral specific T cells
that can recognize that virus,
there are a small number
of cells preexisting
in our body that can recognize that virus,
but what these cells start to
do is undergo clonal expansion
and one cell will replicate to two cells,
two to four, four to eight and so on.
This exponential growth
of T cells will occur
and the B cells as well.
I'm just focusing here on
the T cells in this graph,
but you'll start to
see this rapid increase
in the number of cells
that recognize that virus.
They are specific for that virus.
And this is during the
acute phase of the response
and of the infection.
And usually for most common colds,
the infection is cleared
within a couple of weeks
and following the resolution
then of that infection
with the control of the pathogen,
what you see then is the second phase,
which is the contraction phase.
And while you generated
millions and millions
of these viral specific T
cells during the first phase,
most of these cells are
actually going to die
during the resolution phase.
And what you're left with then is
as you enter the third phase,
which could be many weeks to
many months after infection,
is what we refer to as the memory phase.
And this is where the formation
of these long-lived memory T cells
and memory B cells is occurring,
is during this latter
phase of the response.
So you can think of these
cells that form early
and develop a lot of important functions
and deploy lots of weapons
to eradicate the pathogen.
We refer to this early phase
as these effector cells,
which are able to fight
the present infection
'cause that's their job.
They're being generated to
fight the present infection.
But over the course of
the contraction phase,
what you're left with
then is a smaller number
of these cells that go on
to seed the memory pool.
And these memory cells
then are what are you used
to fight the future infection.
So now you can see how our
immune systems are able
to do both job number one, to
fight the present infection
and job number two, to
fight future infections
through the course of this primary,
this first exposure to the pathogen.
Now if we look at this
at a cellular level,
you can see that these T
cells initially start off
as what we refer to as naive
'cause they haven't seen
that the pathogen that
they might recognize.
But upon that infection
and getting activated,
recognizing that pathogen,
they then start to become activated.
They start to proliferate and expand.
And as we had talked about,
developing into these effector cell,
but only a very small number
of these cells will survive
to go on to be the memory cells.
And this number of five to 10% surviving
has been seen reproducibly
across many different types of infections.
So this is, it's a very common attribute
that you generate millions
and millions of T cells
during the primary infection,
but only a very small
number of those cells go on
to become your memory cells.
And that was a fascinating question.
What is the reason why only a
small percent of these cells
are able to give rise to
these long-lived memory cells?
They are endowed with this ability
to provide this longterm immunity.
What are the decisions and
the processes that are guiding
the formation of the small
pool of memory cells?
And many years ago,
we knew the kinetics of
this immune response,
but we didn't know really
any of the molecular pieces
or parts of the pathway that were involved
in making this decision of which cells
were going to give rise
to the memory T cells.
And so many years ago,
we set off to try to tackle
this by looking at the genes
that were expressed in these
long-lived memory cells
versus this pool of effector cells
that we knew was gonna give
rise to the memory cells.
But most of these cells were going to die.
And we were trying to ask,
what genes might be involved in this life
or death decision that these
effector cells are making
to determine which of these
cells were going to go on
to give rise to the memory pool.
And one of the genes that we identify,
and this was many years ago,
but it was still a fundamental
finding to the field,
was a discovery that the cells,
that the memory cells expressed
high levels of a receptor
called interleukin-7 receptor.
And this was really important
for the memory T cells survival.
And when we started to
then look more closely
at these effector cells at the expression
of this IL-7 receptor,
what we found was that
there were indeed a subset of cells
that expressed higher
levels of IL-7 receptor,
like these more mature memory cells.
And that what we found
was that this was able
to identify and distinguish the precursors
or progenitor cells of this
effector pool that would go on
to give rise to this long-lived
memory T cell population.
So during the course of
this immune response,
the population of effector
T cells is heterogeneous
and there are some cells that are forming
but they don't have the
potential to give rise
to this long-lived pool of memory cells.
But there's a small subset of cells,
these memory progenitor cells,
that are becoming destined
and determined to give rise
to this long-lived memory pool.
And part of that involves the
expression of IL-7 receptor.
So how do these memory
progenitor cells form?
If they're important for
establishing this memory pool,
then how are they forming
earlier in the immune response
during the first few days of infection?
And so by having this tool
now being able to distinguish
these memory progenitor cells
from these other effector
cells that we refer to
as terminal effector cells
that would die after the infection,
we're able to then
compare these populations
and start to identify the genes
that made these cells
distinct from one another.
And many of these genes that
we found that were associated
with being a memory progenitor
or a terminal effector cell
started to then uncover
many of the pathways
that were involved in the formation
of these two different
types of T cells that form:
the memory progenitor cells and
the terminal effector cells.
What this did was then
to help us to elucidate
the transcriptional
programs that were helping
to create the development of
these memory progenitor cells
and these terminal effector cells.
And these transcriptional
programs ended up having
opposing functions to orient
these alternative fates
that were being produced
during this primary immune response.
We also identified,
through the dissection of
these different cell types,
many of the signals in the environment
that are being produced
during the infection
that would instruct these
different cells to form.
And while we identified
that many of the inflammatory mediators
are associated with infection,
helped to drive these terminal
effector cells to form,
that will be very important for fighting
the present infection but again,
they lose the ability to give rise
to this long-lived memory pool.
Many of the inflammatory mediators
produced during infection
will help to support
these terminal effectors.
But what we also found that
was very counterintuitive
is that anti-inflammatory
factors can actually help promote
the formation of these
memory progenitor cells.
And so there's a balance
between inflammation
and anti-inflammatory
signals that help to balance
this decision that creates
these effector pools
with these diverse fates,
these different longterm fates.
And I just wanna end
with then thinking about
how this then relates
to some of the questions
that we're thinking about today,
especially in light of COVID-19,
which is that what are gonna
be the right types of immunity,
longterm immunity that
we need to establish
with the vaccines that are
going to be tested in people?
While memory T cells and
memory B cells are essential
for providing us with
this longterm immunity,
I want you to also appreciate
that there's many different
types of memory T cells.
And actually what happens
after our first exposure
to that pathogen is
that we shield our body
from the outside in with
lodging memory T cells
in different compartments in our body.
And as you can see here,
virtually, every tissue in our body
can harbor different
types of memory T cells
and some memory T cells circulate
throughout our blood system
and they might go into tissues
and then go back into circulation.
We refer to those as
circulating memory T cells.
And there's many different
types of memory T cells
within the circulating pool.
But there's also a very important
form of what we refer to
as tissue-resident memory cells.
We have some memory cells that
will enter the tissue upon
the first infection and
they'll remain there
for very long periods of time, years,
sometimes even decades,
after that first exposure.
We see these long-lived
resident memory T cells
in many different tissues,
largely our barriers.
We see them in our lungs,
we see them in our
intestines, in our skin.
So they can lodge themselves
longterm and reside longterm
in our tissues that
provide barrier function.
But they also are found
in other internal organs
such as our brain, our kidneys, our liver.
So we can see these long-lived
resident memory cells
in almost every tissue
that's been studied.
And it's the cooperation of
these circulating memory T cells
and these tissue-resident memory
cells that helps us again,
provide that shield, having
protection from the outside in
because these memory T
cells that are our barriers,
they're there at the portal of infection.
They're right there at the
front line when that pathogen
should enter and their
immediate responses help
to provide protection to that tissue.
So as we think about what types
of memory we're gonna need
for COVID-19, for protection in COVID-19,
now we need to be thinking about forming
the circulating memory
and the humoral immunity
such as what's provided by our B cells.
But also probably very important
will be these lung-resident memory cells
that these memory T cells
that can persist in our lungs
and provide protection
to respiratory infections
when we inhale those pathogens.
And so I think this is
gonna be an important aspect
that we think about is what
types of memory T cells
are induced by COVID-19,
and which types are gonna
be the most protective
for longterm immunity to this virus.
And so, with that, I just
wanna thank you for your time
and thank my lab for all the ideas
and great work that they do.
And of course, funding
from the NOMIS Foundation
as well as the NIH,
which has been essential to
allow us to do this work.
So thank you.
(upbeat music)
