Recall, please,  that we were discussing last time  
the fact that the immune system makes a wide diversity of antibody  
molecules.  And,  by the way, a synonym for an  
antibody molecule is an immunoglobulin.   
Recall that we used that word very briefly.  Another word we use,   
by the way, was the word antigen.  And, an antigen is a functional term.   
That was pretty funny.  An antigen is a functional term.   
An antigen is an agent that provokes an immune response.   
And, the term antigen doesn't really refer to any specific  
chemical structure.  It doesn't even have to be a  
protein.  Antigen simply refers to some chemical entity that creates  
some response from the immune system.  We also use the word in  
passing, epitope.  And, an epitope refers to a small  
region, for example,  a protein against which an antibody  
has developed reactivity.  And if you recall our discussion  
last time, a protein obviously of some size has multiple distinct  
epitopes, each of which can be recognized by a distinct antibody  
molecule.  And,  for us, could we,   
I'm sorry if I got all this political discussion  
started, thank you.  Thank you.  An epitope,   
from the point of view of a protein is an oligo peptide.   
So, a stretch of amino acids of maybe ten, or 12,   
or 15 amino acids forms an epitope.  And therefore, you can imagine  
there are multiple epitopes on the surface of a protein.   
In fact, antibodies can sometimes recognize the internal parts of the  
protein because protein can sometimes become denatured  
or degraded.  Indeed, as we will discuss shortly,   
proteins also become cleaved into oligo peptides.   
These oligo peptides can come from any part of the protein,   
to state the obvious, and therefore there might be internal epitopes  
that exist in a protein that are not normally exposed by the native  
protein.  Recall that we were dealing with the issue of how the  
immune system is able to create a wide diversity of antibodies,   
immunoglobulins would share in common a constant domain.   
And the constant domain is formed by these invariant regions of the light  
and the heavy chains.  We call this the heterotetramer in  
contrast to the variable domain up here which recognizes the antigen  
that initially provoked the production of this antibody molecule.   
And, the immune system may at any one point in time be making hundreds  
of thousands, maybe even millions or tens of millions of distinct  
antibody species that differ one from the other by the antigen  
recognition site here at this part of the antibody molecule.   
And recall as well that since these are proteins, the  
antigen-recognizing pocket is itself an oligopeptide,   
which combined in some complementary fashion to whatever antigen  
initially provoked the synthesis of this antibody molecule.   
At the end of last time,  we discussed the fact that  
antibodies are made by B cells,  and the fact that in the disease of  
multiple myeloma,  one ends up with a monoclonal  
disease, that is to say,  one of a vastly heterogeneous  
population of B cells begins to proliferate uncontrollably.   
And now, all of its descendants make a single antibody species.   
And that single antibody species consists once again of a heavy and a  
light chain, whose identity is created by the antigen-recognizing  
pocket that it happens to carry.  And this begins to suggest a notion  
of clonal expansion.  By that, I mean the following.   
Let's imagine a scenario where we start out with a naīve immune system  
where we have a whole series of different B cells.   
And this series goes here from 1-15,  but in fact this could go from one  
up to a million.  And each of these antibody  
producing B cells,  or each of these B cells,   
has in principle the ability to respond to a different antigen.   
Let's just imagine that.  And now, what we can imagine is  
that an antigen such as,  for example, poliovirus comes into  
the body, and it is recognized by two different clones of these B  
cells.  And that recognition,  we can imagine, acts as a mytogenic  
signal, a growth stimulatory signal for these two particular clones and  
B cells.  It almost acts as if it were a growth factor.   
But of course, we're not talking about growth factors here.   
We're talking about antigens,  including antigens brought into the  
tissue by a foreign infectious agent.  And therefore,   
the recognition of the antigen by these two B cells may thereafter  
provoke their clonal expansion.  By that I mean to say that they  
will preferentially begin to proliferate whereas all the other B  
cells, which are not in any way responsive to that antigen will just  
sit there like bumps on a log.  And, if there is,   
therefore, clonal expansion,  now there will be a much larger  
number of cells in the immune system that are capable of producing the  
antibody that recognizes its provoking antigen.   
Again, recall that this number may go up to a million.   
This is just a great simplification.  Now here, we use the word plasma  
cells.  And in fact,  if one wants to get the nomenclature  
very proper, the plasma cells are the products of B cells which mature  
into the antibody producing plasma cells.   
They are very close on the same lineage of cells,   
and what that means in the end for us is if once there's an active  
immune response,  there's been the preferential  
expansion of certain sub-populations of B cells and plasma cells,   
and other ones of them which don't recognize these antigens just sit  
there are underrepresented in the total population of cells.   
Still, the fundamental question that we posed last time  
was the following.  If it's the case,   
and it happens to be that each of these B cells makes an antibody  
having a distinct reactivity,  a distinct ability to react to one  
or another antigen how do they make so many different kinds of antibody  
molecules.  How do they know how to do that.  We argued that it's  
implausible that the amino acid sequences of each antibody molecule  
are encoded in the germ line.  Why?  Well, if there are indeed a  
million or even 100 million distinct antibodies can be made by the immune  
system, clearly there can't be 100 million genes,   
each of which is dedicated to the production of a distinct  
antibody molecule.  And the solution to this puzzle was  
first worked out by Susumu Tonegawa already more than 20 years ago who  
happens to be in our biology department.  And what he discovered  
was the following,  that the way that the antibody  
producing genes are organized is really quite extraordinary  
and unusual.  Here's the heavy chain of the gene,   
and keep in mind that there's a heavy and a light chain gene.   
The heavy and the light chain genes are in different chromosomes.   
And therefore, the genes that are responsible for encoding these two  
proteins, the heavy and the light chain, they're on different  
chromosomes, and encode by different genes.  OK, so what Tonegawa  
discovered was the following,  that the variable region of an  
antibody molecule which is at its end terminus is encoded by small  
segments of DNA that are carried in one very large genetic locus,   
an immunoglobulin locus.  And what happens in humans is the  
following.  There are in humans rather than mice,   
this number should be 100 in humans,  there are 100 distinct V segments  
that are encoded in this antibody locus.  Each one is roughly the same  
size, and they're located in a large tandem array.   
Similarly, there are in humans 30 of these desegments.   
The numbers change here if one goes from mouse to human,   
but that's irrelevant.  And, there are six of the J  
segments.  And,  much of the antigen-recognizing  
capacity, much of the variable region is encoded in the green and  
the blue region of the gene,  and the encoding happens as follows.   
 There is a combinatorial fashion the  
random fusion of V,  D, and J segments.  There are  
specific, highly specialized enzyme that will choose one specific V  
segment, one specific D segment,  and one specific J segment,   
ostensibly on a stochastic basis,  a totally random basis, and fuse  
them together.  And if that happens,   
and the intervening DNA sequences are discarded,   
then right away we can see that through the combinatorial  
mathematics that results from this,  there is the possibility for having  
100 times 30, which is 3,  00, times six, which is already 180,   
00 distinct combinations encoding the reading frame of this particular  
antibody molecule.  Here, I've just said V23,   
I guess, D7, J2.  But again,  let's imagine, which is  
approximately the case,  that each of these combinations can  
be fused with roughly equal probability.   
What happens subsequently,  then, is that this variable region  
sequence, which has been formed by fusion, is then the transcript that  
comes from that is spliced to the constant region which is towards the  
C terminus.  So here,  when we talk about the V,   
D, and J segments, we're talking about the segments that are encoding  
this portion.  Here's this portion of the antibody molecule.   
Keep in mind, from here on down,  we're talking about constant region  
segments which are not affected by these combinatorial fusions.   
And, in the overhead I just showed you, I was just talking about how  
the heavy chain gene is rearranged.  And what that results as a  
consequence is the following.  This is just another version of  
what I just showed you before,  where the V, D, and J segments  
become fused randomly to one another creating a V, D,   
J fusion thing, which then by splicing is fused to the constant  
region which here is called C sub-mu.   
For reasons of why it's called sub-mu I'll mention in a moment.   
And this is the actual messenger RNA which then goes into the  
cytoplasm.  And what we can now imagine is the following,   
that when the immune system first begins, it randomly fuses whole  
series of V, D,  and J segments together,   
and all kinds of combinations.  The same happens in both the heavy  
chain and the light chain,  although the light chain is slightly  
simpler.  But that's irrelevant for us  
conceptually.  And then,  we end up having hundreds of  
millions of distinct V cells,  each of which has a different  
combination of heavy and light chains because keep in mind the  
light chain genes are also being rearranged combinatorially.   
They're also being fused.  And therefore, we can have 180,   
00 distinct heavy chains, and I forget the exact number for the  
number of light chains.  It's a bit less,   
but we can multiply those two combinations by one another because  
keep in mind that the gene encoding the heavy chain here in its variable  
region, and the gene encoding the light chain in its variable region  
are organized on separate chromosomes.  And,   
they're fused together.  These segments are fused together  
randomly.  So,  the total number of antibody  
molecules we can make is 180,  00 distinct kinds of these.   
And, I've just slipped up in knowing the total number of these that can  
be made, although we could figure it out shortly if it were really  
important.  But once again,  the number is in the many thousands.   
And therefore, overall, the total number of distinct antibody  
molecules one can make on the basis of this is this.   
Did I get the math right,  60 by 30, 18,000.  It's 18,   
00.  So, there's 18,000 distinct of these that can be made,   
and the number of these,  I think, is closer to 10,000.   
I forget, but multiplied,  let's call it 10,000 for a moment.   
That's not the right number.  There's 10,000 different ones of  
these, and 18,  00 of these that can be made.   
Multiply them together, and you get the total number of combinations of  
antibody molecules it could make because it is the case that the  
antigen recognition site here is created cooperatively,   
collaboratively, by the heavy and light chain.  You had a question?   
So, the gene is rearranged,  and when the rearrangement occurs,   
on V segment is fused to one D segment, is fused to one J segment.   
And all of the extraneous segments that are between them have been  
deleted from the chromosome.  So, this leads me to a second point  
I wanted to make,  and that is that here we are dealing  
with a process of somatic mutation.   
We talked about last time or the time before last the fact that  
somatic mutation is generally a process that can lead to cancer,   
i.e. the mutation of germ line genes that are in one way or another  
corrupted by random mutational processes.  But here,   
I'm talking about a somatic mutational process,   
which is highly directed and highly organized, and focused on creating a  
series of rearranged genes that can then serve as the template for the  
production of an antibody molecule.  So here, let's just look at this  
again.  Here, I'll tell you,  there are many V genes.  There are  
many D genes, and there are many J genes.  And, this is the embryonic  
DNA.  After large segments of the immunoglobulin locus are deleted,   
and then the surviving V, D, and J segments become fused in the DNA  
directly to one another.  And when that happens,   
the resulting B cell DNA can be transcribed, and via splicing create  
an mRNA where the region in between the J's chain and the constant  
region chain called,  here C, is further deleted.   
So, each messenger RNA has one V,  one D, and one J segment together  
with a constant region segment.  There are yet other processes that  
further diversify how many different variable regions can be encoded.   
One of them is the following.  It turns out that the process by  
which the V and D,  and the D and J genes are fused  
together, those segments are fused together, is a bit sloppy.   
And therefore, sometimes the fusion will occur creating a sequence of  
nucleotides that has a nonsense codon in.  Sometimes it will create  
a coherent reading frame that creates yet another kind of amino  
acid sequence there.  And therefore, this is not a highly  
ordered process in the sense that these micro-architecture of the  
points with the V and the D,  and the D and the J are fused is a  
little bit chaotic.  So that creates even further  
randomization of the nucleotide sequence.  And then,   
finally, once this gene has been created, there is a process which is  
called hypermutation,  where through mechanisms which are  
not well understood,  the nucleotide sequence of this  
region is actually further changed.   
It's mutated by certain enzymes.  For example, there's an enzyme  
called cytidine deaminase,  which takes off the amine group off  
of the cytidines in that region,  and thereby effectively converts the  
C's in that coding region more into having a T coding capacity.   
This happens somatically,  and here once again I'm talking  
about a further dimension of diversification.   
One of the dimensions diversification,   
first of all, the V and the J chains rearrange independently,   
randomly, and stochastically.  Secondly, the joining of the  
segments is a bit sloppy.  And thirdly, there is somatic  
hypermutation.  There's an enzyme like this which  
is actually an actively mutagenic enzyme which fiddles around with  
some of the C's in this portion of the gene, thereby further  
diversifying the coding ability of the immunoglobulin gene that's  
encoded by the cell.  And what this means is the following,   
that if we imagine this scheme here where each of these B cells  
recognize it's a different antigen,  initially there may be 100 million  
distinct B cell clones that are created, each the consequence of a  
different random mutation.  That happens early in the  
development of the immune system.  Thereafter, there are certain  
selective processes there at play.  One important selective process is  
the elimination of B cells that have failed to make nicely rearranged  
antibody molecules.  What do I mean by that?   
I told you how sloppy the V,  D, J joining is.  And therefore,   
many of these joinings could create reading frames that are incoherent  
with stop codons in the middle.  And therefore,   
those cells which happen to have created antibody molecules which are  
highly mutant and clearly structurally defective are  
eliminated.  So,  one prerequisite for the survival of  
these B cells early in the development of the immune system is  
that they've learned how to make functional heavy and light chains.   
If they don't, they're right away wiped out.  They're eliminated.   
Here's another very important prerequisite for survival,   
that these B cells don't make antibodies that react with antigens  
that are native to the body's own tissues.  What do I mean by that?   
Well, one of the wonders of the immune system is the following,   
that it can recognize foreign antigens that are brought into the  
body from the outside including,  for example, the epitopes on the  
surface of polio virus particle.  It can recognize many different  
viruses, surface antigens present on the surface of bacteria,   
and fungi, and all kinds of other infectious agents.   
But importantly,  the immune system also sees hundreds  
of millions of different epitopes of the proteins that are present  
endogenously, native proteins in our tissues.  A priori,   
the native proteins,  what's called our own self-proteins,   
are perfectly qualified to function as antigens.   
And yet, the immune system rarely develops strong reactivity against  
them.  Thus, the immune system has the ability to recognize self versus  
non-self.  What do I mean by self versus non-self?   
Self are the body's own native proteins, which are in principal  
conceivably antigenic.  Non-cell are foreign invaders that  
bring strange epitopes into the cell.   
And what happens is that B cells,  which make antibodies, that  
recognize native proteins in our tissues are, if things are working  
well, rapidly eliminated early in the development of the immune system.   
What happens if that elimination fails to occur properly?   
If it fails to occur, one has the process of autoimmune disease.   
And, there are multiple autoimmune diseases.   
Type one diabetes,  early onset diabetes happens when  
the immune system recognizes antigens that are present in the  
islet cells in the pancreas that make insulin.  Rheumatoid arthritis,   
which inflicts a large portion of the elderly, happens when the immune  
system recognizes antigens that are present normally in the cartilage in  
our joints.  Lupus happens when,  it's an autoimmune called lupus  
which is often fatal,  happens when the immune system  
recognizes proteins in many different tissues.   
And once again,  in all of these cases,   
there is a breakdown of the mechanisms governing immune  
tolerance.  And what do I mean by tolerance?  I mean the mechanisms  
whereby the immune system tolerates native antigens,   
but is conversely intolerant of foreign antigens.   
The word intolerant is not used in immunology, but I'm just using it  
for the sake of explanation here.  So, immune tolerance is a very  
important area of current immunological research.   
We don't really understand why we don't have much more autoimmune  
disease than we do.  And by the way, only listed two or  
three of the most common kinds of autoimmune diseases that happen with  
the mechanisms that normally guarantee immune tolerance failed.   
And therefore, these B cells survive are ones that make  
functional antibodies and those whose antibodies do not recognize  
self-antigens.  They are permitted to survive,   
and once again, we imagine that those that happened to make  
antibodies that recognize particular foreign antigens undergo or enjoy  
clonal expansion.  During the development of the  
immune response,  there is a further diversification  
of the antigen-recognizing domain of the protein by hypermutation.   
And therefore,  descendants of these initially  
developed cells,  which have begun to expand because  
they make an antibody,  may develop antibody molecules that  
are even more able to bind avidly to the antigen.  It could be that  
initially, these antibody-producing cells make antibody molecules that  
bind nicely to the antigen but not really avidly.  Avidly means  
really tightly.  And, that's enough to get their  
clonal expansion going,  but during the process of clonal  
expansion, this hypermutation creates further variants of these  
cells, further mutates their antibody producing genes so that  
some of the descendants of these cells will produce antibody  
molecules that bind even more tightly and specifically to the  
provoking antigen.  And when that happens,   
the quality of the antibodies is improved progressively.   
Now clearly, the somatic hypermutation once again,   
it's a random hypermutation.  And those clones of cells in which  
the hypermutation created less effective antibodies will not have  
their proliferation stimulated.  Those clones of cells whose  
antibodies make more and more tightly binding antibodies will  
preferentially have their proliferation stimulated.   
And as a consequence,  they will now be the ones that are  
favored to yield the plasma cells that produce large amounts of  
antibody molecules.  So, we have now this very unusual  
and very interesting way by which B cells and plasma cells are able to  
create a wide diversity of antibody molecules.  Now,   
one of the interesting things,  actually, is the fact that this  
constant region contains one of a variety of distinct  
constant regions.  Initially, when one produces the  
first immune response,  the first immune response as we said  
before produces a constant region which is called CM,   
and I had the right overhead this morning.  Ah, here it is.   
Here's the way the genes are actually rearranged.   
Here's the rearranged V,  D, and J, and here's the splice to  
the constant region.  And downstream are a whole series of  
constant region segments.  What's the first one: CM.   
I told you about that before.  Thereafter, C sub delta, C sub  
gamma-3, gamma-1,  gamma-2, gamma-8, and so forth.   
And therefore, the initial event can create an ig-mu, an IgM  
antibody molecule.  The mu region creates an IgM.   
Later, as the immune response develops further,   
this mu segment may become deleted.  And now, the splice may occur to a  
delta or a gamma change.  And therefore, if the intervening  
constant region is changed,  you might get what's called an IgG.   
An IgG is an immunoglobulin which is produced when this  
antigen-recognizing region becomes spliced down to here or here by  
virtue of the deletion of these intervening constant  
region segments.  What's the purpose of what's called  
class switching?  Because these are different classes  
of antibodies,  because they have different  
functions.  Note importantly that when this class switching occurs,   
it has no effect on the antigen-recognizing site of the  
antibody molecule.  Rather, it affects the constant  
region of the antibody molecule.  Well, how does that work?  The  
initially made antibody molecule,  I told you, is IgM.  And in fact, if  
you look at the structure of IgM,  it looks like this.  Here's, let's  
say, a B cell,  and the IgM molecule is actually not  
secreted into the extra cellular space like a soluble  
antibody molecule.  Here's what IgM looks like from very  
schematically IgM has our standard antigen-recognizing site,   
but IgM is embedded in the plasma membrane of the B cell exactly the  
way that a growth factor receptor is embedded in the plasma membrane of a  
B cell.  But keep in mind that I just said that this IgM molecule has  
an antigen-recognizing domain up here, which is exactly the way we  
described it before.  So, the antigen recognition is not  
affected by whether we have an IgM molecule here.   
Only the location of the antibody molecule, and as I'll show shortly,   
the function of this antibody molecule is affected by this IgM.   
Later on, descendants of this B cell will mature into those that  
secrete IgG molecules into the plasma.   
So, here's a maturation that's going on.  But look here.   
Once again, the antigen-recognizing domains of this IgG are unaffected  
by this conversion.  Here, the constant region is  
tethering the antibody molecule to the plasma membrane.   
Here's the antigen-recognizing sites.   
After this maturation occurs,  the secreted IgG molecules, which go  
into the solution,  have identical antigen-recognizing  
sites, but now they're soluble proteins.  Well,   
you'll say, why does the immune system do that?   
And, it goes back to an overhead I showed you just moments ago in which  
there was a puzzle implicitly created by the image on the overhead.   
And here it is.  Let's look at this for a moment.   
What detail is now explained in this scheme?  What detail is now  
explained?  I told you that B cells can be stimulated by certain  
antigens.  Let's imagine that each of these B cells made only secreted  
antibody, OK, instead of making cell surface antibody because the cell  
surface antibody,  which is being made in this scheme,   
is actually the IgM molecules.  Let's say this B cell over here is  
making an antigen.  I'll just draw it as,   
there's the antigen, is making an antibody against this antigen,   
and it's secreting antibody against this.  And I'd just argue that the B  
cell that makes good antibody is favored.  It has its proliferation  
stimulated, right?  That's what we talked about.   
But if this B cell sends all of its antibody into the plasma,   
how is it going to know that it's making a good antibody?   
It can't because all of the antigen recognition is happening by the  
secreted antibody.  So, what happens with the IgM  
molecules.  The first antibody molecule this produced is IgM.   
And, it stays tethered to the plasma membrane of the B cell.   
It's a transmembrane protein, and it functions much like a  
growth factor receptor.  That is to say,   
when the antigen binds out here,  there are signals that are radiated  
into the cell that induce the proliferation of this cell.   
And now, these cells that produce the antigen-recognizing IgM  
molecules on their surface can now have their proliferation stimulated.   
That solves the puzzle here which is created by this scheme.   
If all these B cells just made secreted antibody like this,   
then there would be no way to encourage their proliferation  
because there would be no way of telling this B cell you're  
doing a good thing.  Keep making more of these antibody  
molecules.  Here,  the antigen-recognizing capability  
is embedded in the plasma membrane.  And when an antigen binds this, the  
IgM molecule's organized so that now growth stimulatory signals are sent  
into the cell which cause this cell to begin to proliferate,   
producing more IgM containing cells which are further stimulated  
to proliferate.  And ultimately after this has gone  
on for a while,  there is a class switching which  
deletes the IgM region of the gene chain region, and causes a  
conversion to IgG.  Again, the conversion from here to  
here doesn't change the antigen-recognizing capability of  
these two antibodies.  It just makes a cell surface  
transmembrane protein or a secreted protein.  (pause)  
 No, the VDJ choice happens in the  
nucleus.  It's a fusion of different DNA segments, and when it's  
transcribed, that fused VDJ is now spliced to a constant region segment.   
The choice of VDJ is a fusion of DNA segments.  It happens in  
chromosomal DNA.  It results in the deletion of all  
the segments that aren't used.  So, all that's left in the  
immunoglobulin locus of a B cell is a DNA segment encoding V fused to a  
DNA segment encoding D,  fused to a DNA segment encoding J.   
So now, you have a new somatically mutated immunoglobulin gene,   
lest there be any residual confusion about that.  So,   
you see the elegance of this class-switching thing.   
Now there's yet other constant region segments that are used for  
other purposes.  For example, when you have  
allergies, there's an activation of the igE antibodies.   
When you have secreted antibody production in the colon,   
igA is used more for that.  So, different ones of these  
constant regions are used for different immunological applications.   
The IgM molecule,  as I've said, is used here just as a  
way of telling the B cell that it's done well by making the right kind  
of antigen-recognizing site.  The real business of creating  
antibodies is the soluble antibody production, the immunoglobulins,   
or the gammaglobulins because the vast majority of antibodies floating  
around the blood plasma are in fact IgGs.  The IgMs are,   
as implied by this, actually just largely tethered to the surface of  
cells.  So, this really is an extraordinary,   
elegant way of creating essentially hundreds of millions of different  
antigen-recognizing domains each created collaboratively between a  
heavy and a light chain.  And once these antigen-recognizing  
domains are created through changes in DNA structure,   
then they can be used for different immunological applications,   
driving B cell proliferation,  secreting soluble antibodies that  
are used to neutralize virus particles in the blood,   
or if they're hyperactive to create allergic reactions or to create  
immunity in certain regions of the gut and so forth.   
So, this class switching doesn't change the antigen-recognizing  
capability.  It just changes the utilization of how already-developed  
VDJ segments and their antigen-recognizing capability are  
exploited by cells of the immune system.   
Now, one thing that's not really clear by all this is how all this  
develops at the cellular level because what I've talked about until  
now is called humeral immunity.  Well, we talk about somebody having  
a good sense of humor.  But the actual original meaning of  
the word humor in Latin was fluids that were fluxing through your body,   
and were responsible for your different mood states.   
So, if you were depressed or there just was a national election,   
there would be black fluids, black humors coursing through  
your blood.  And if you were in a good mood,   
there were other humors coursing through your blood.   
And that leads through this etymology to the term of humeral  
immunity, which is to say the soluble immunity,   
i.e. the production of soluble antibody molecules.   
But I will tell you that there's a second arm of the immune system  
which is equally important,  and that's called cellular immunity.   
And, to make a long story short,  and we'll elaborate it on Monday  
briefly.  Cellular immunity is largely created when you have a kind  
of immune cell that's called a cell rather than the B cells we've been  
talking about until now,  which is able, and this cellular  
immunity is among other things, cytotoxic.   
And, it can recognize a second cell over here.  Here's a second cell.   
This is its target cell because the second target cell is displaying on  
its surface certain antigens.  So, antigens are being displayed on  
the surface of the target cell.  I've indicated them here as just  
little, blue strokes.  And the T cell is able to recognize  
these antigens on the surface of this cell here,   
and is able to kill this cell through a series of interesting  
mechanisms.  This doesn't involve the intervention of soluble antibody  
molecules.  Here,  we're talking about one cell  
recognizing another,  and it turns out to be very  
important for antiviral defenses.  I've told you one way by which  
antiviral defenses are achieved.  Soluble antibody molecules are  
secreted into the blood plasma like IgGs.  They recognize an epitope on  
the surface of a virus particle.  They glom onto that epitope on the  
surface of the virus particle,  and they neutralize the virus  
particle.  And,  that's very important.   
We started out in our discussion of poliovirus talking about that.   
But this also turns out to be very important.  Why is it important?   
For the following reason: when this cell, let's say this cell is  
infected by poliovirus on the inside.   
It turns out, interestingly enough,  that the cell has a way which we'll  
discuss of processing poliovirus polypeptides, viral polypeptides,   
and displaying them on the cell surface.  In other words,   
the cell can chew up some poliovirus proteins, put them to the outside,   
and tell the outside world, these are the kinds of the proteins that  
are being made right now inside of me.   
You the immune system can't really look through the plasma membrane so  
I'm going to tell you this is what's going on inside of me.   
There are poliovirus proteins being made as we speak.   
On the outside of the cell,  these are displayed even though  
poliovirus replication is recurring exclusively inside the cell.   
A cytotoxic T cell here may recognize these antigens on the  
surface of the poliovirus infected cell, and proceed to kill the cell.   
Why is that interesting or important?  Because the cytotoxic cell will  
kill the virus-infected cell while the virus infection is still in full  
swing.  And therefore,  by killing the virus-infected cell,   
it will abort the entire bioreplication cycle because the  
virus won't have enough time to replicate or proliferate inside the  
infected cell before it happens.  It's preemptively killed by the  
cytotoxic T cell.  And in fact, this way of eliminating  
viral infections from our body is as important and often more important  
than the neutralization of soluble virus particles in our plasma.   
And all that gets now to have us focus increasingly on the mechanisms  
by which antigens are recognized and processed so that the immune system  
can begin to respond to them.  So, I want to get into that now,   
into the aspects in which we look at the cellular arms of  
the immune system.  The most important thing initially  
in the immune response is that let's say  poliovirus particle is  
recognized and digested by certain phagocytic cells of the immune  
system.  What's a phagocytic cell: a cell that is able to gobble  
up other things.  So, a well-known phagocytic cell is  
a macrophage.  And there you can see the term phagocyte,   
macrophage.  Phagos means to chew up or to swallow,   
so macrophage might see a particle like this surround that particle,   
and then internalize that particle and digest it,   
let's say a poliovirus particle.  Macrophage could envelop a  
poliovirus particle and internalize it.   
It could do the same thing with a bacteria.  Here,   
we'll use as an abbreviation for macrophage this.   
So, that's macrophage.  There are yet other even more  
important phagocytic cells of the immune system that are called  
dendritic cells.  Now, these cells gobble up whatever  
happens to be around them.  They don't care.   
They are promiscuous sewer,  gutter trollers.  Whatever happens  
to be around, they will gobble up whatever happens to be around.   
They'll put it inside of them,  and now they do something really  
interesting.  The dendritic cells,  the macrophages, the phagocytic  
cells, they don't digest the internalized particles down to amino  
acids.  They digest the virus particle down to oligopeptides.   
Usually if 10, 12, 14 amino acids long: very important.   
So they don't make amino acids.  They make oligopeptides.  Why are  
they doing this digestion?  Because these cells are  
exhibitionists and they want to show the rest of the world what they've  
just swallowed up.  It's really important to them.   
Go figure.  So,  what do they do?   
They take these oligopeptides that they've just internalized and they  
put them on the cell surface via molecules which are called MHC class  
2.  MHC class 2 is the name of these molecules, and these are cell  
surface receptors.  And, these MHT C class 2 molecules  
have included in them an oligopeptide that has just been  
produced by the proteolytic cleavage of an internalized infectious agent,   
let's say.  And so, the macrophage has many of these MHC class 2  
molecules on its surface,  and it displays to the outside world  
what it has just captured in terms of these oligopeptides.   
And these oligopeptides are,  by the way, roughly the size of an  
epitope.  Therefore,  this macrophage is just so excited.   
It's like a little kid who has just found something,   
so excited to show the world what it's just found and gobbled up and  
processed.  And over here is a class of cells which are called T helper  
cells.  And the T helper cells are interesting in their  
own right, right?  The T helper cells have evolved  
through a mechanism that is similar to and parallel to the evolution of  
the B cells.  As a consequence,  there are many different kinds of T  
helper cells.  Each one,  so TH-1, TH-2, TH-3, each of which  
displays on its surface a T cell receptor.   
What kind of T cell receptor does it display?  A T cell receptor that has  
gone through exactly the same kind of hoops that the antibody genes  
have gone through.  That is, each T cell expresses on  
its surface an antigen-recognizing receptor just like the IgM molecule  
except it's made by T cells and it's created by these stochastic  
processes of fusing DNA segments.  So, each of these T cells,   
and again, there are millions of them, has a different T cell  
receptor with a different antigen-recognizing capability.   
And here's what happens in the immune system.   
Let's imagine,  as I say every year,   
that we're in a Middle Eastern bazaar, and that Middle Eastern  
bazaar, here are all the shops on the sides on the sides of this long  
bazaar.  It's sometimes called a shuk or a suk.   
And here we're going to have a macrophage or a dendritic cell  
moving through the bazaar.  Hanging out in front of the stores  
are a whole bunch of T helper cells.   
 Business is slow,   
so all these T helper cells are just hanging out in front,   
and as is not the custom in this region, let's pretend all the T  
helper cells are girls just for the heck of it.  It doesn't make any  
difference.  And each of these T helper cells is displaying its own T  
cell receptor which has arisen through stochastic mechanisms and  
which recognizes a different oligopeptide.   
And here we have now the macrophage coming through like a vendor,   
a street vendor, saying, look girls,  look at the epitope I just gobbled  
up and produced.  Isn't it great?  And,   
it's using its MHC class 2 molecules to present, it's like hands,   
presenting the epitopes.  It's flogging them like a street vendor,   
and it walks down through this bazaar, and each of the T helper  
cells, they're congregating along the sides of the road,   
and most of them say look at this drip.   
Look at the garbage he's selling us today.  I am totally uninterested.   
He was here last week with some other chump too.   
Let's hope he disappears quickly.  And meanwhile the macrophage or the  
dendritic cell is very anxiously trying to find someone who has even  
the slightest bit of affection or respect for him.   
And this goes on for a long time.    
And finally, the macrophage finds a T helper cell over here.   
So, here's the T helper cell,  and it turns out that by coincidence  
the T helper cell has on here surface a T cell receptor that  
recognizes the epitope that the macrophage is peddling.   
So, here's the macrophage.  Macrophage has on its surface this  
oligopeptide held by the MHC class 2 hands.  So, here's the peptide.   
And this T cell receptor which I'll abbreviate TCR recognizes,   
binds strongly to the epitope that's being flogged by the macrophage.   
And this is, I will tell you honestly, love at first sight.   
She says, oh, I can't believe it.  You're selling an epitope that I  
just happen to love.  This is very exciting.   
And all the other T helper cells say, oh my God,   
what does she see in him?  And she gets all excited because  
there's a direct complementarity.  In fact, to tell the truth, the T  
cell receptor recognizes not only the epitope but also the surrounding  
amino acids in the fingers of the MHC class 2 molecule.   
It's this constellation of things that's recognized by the T cell  
receptor and gets this T cell receptor really excited.   
And what does she do?  Well,  we can't talk about everything  
because this is polite company.  But most important for what she  
does is she begins to proliferate like mad.  Well,   
you know, cells have a limited repertoire of behavioral routines.   
Next time we're going to figure out how this leads to an immune response.   
So, we're going to be on [intention?  all weekend.  
