Well, parts three and four may have seemed to me
to contain an awful lot of miscellaneous information.
So I can only imagine how much you guys might be feeling at this point.
So what I want to do in section five is maybe bring up some review material
and try to put some of the previous material in that context.
And start knitting together a proper context that will help you
understand all of this, again, miscellaneous naming
and highly complex interactions in these systems.
So here's a review figure.
We had this before, during the T cell development.
At this point, it's time to note that we have, again, three types of cells that
are involved in defensive responses-- the T17, Th1, Th2,
and one type of cell that's essentially involved
in downregulating these defenses.
Notice all of our defenders have upregulated
some form of STAT transcription factor, using our famous JAK-STAT pathway.
And so what happens here is we basically have
three different triggers for this pathway.
They'll all be kicked off by slightly different hormones and receptors.
And we have, again, the enzymes from the pathway
will be interacting with whatever STAT is available to them.
And so these cells will be set up to activate
three different kinds of STATs.
All of these STATS will be upregulating molecules used in defense.
But they'll be upregulating different concentrations
of different types of molecules and using different defensive strategies.
Now down here, on the lower left, we have the T regulatory cell.
And a reminder that the T regulatory cell
is different from these other guys in some fairly significant ways.
So here we have our cartoon, and now probably have a better understanding
of this wonderful red plume in the helmet of our T regulatory cells.
Because, notice it starts out with three parts.
It has all three subunits of the IL-2 receptor.
And that means this is ready to rock and roll from the get-go,
as soon as it gets an IL-2 signal.
Thus, T regulatory cells are more sensitive to IL-2,
especially at the beginning of an infection.
And they will, therefore, in some ways have a head start.
So this prevents you from overreacting, reacting to the wrong thing,
reacting to something before you had a chance
to consider whether this is a truly damaging infection, or simply
a bad mistake on the part of your surveillance system.
Also associated with this class of cells, T regulatory cells,
is the production of the immunoglobulin IgA.
Now recall there are two IgA coding, Fc coding sections
in the B immunoglobulin heavy chain gene.
And therefore, it's kind of on the border
between being inflammatory and not so inflammatory.
So that form of the IgA is something that
will be secreted into the lumen of the gut
and possibly be there to fight an infection.
You also have a form of IgA instruction at the end of the B cell heavy chain
gene options.
And this one is a very mild-mannered IgA.
It's probably the sort of IgA that you want to secrete lots of things
to do a boundary defense, without upregulating your immune system
unnecessarily.
Since you can produce up to 15 grams of various types of this a day,
it seems that the T regulatory cell is part
of encouraging the production of this form of IgA
in the absence of any illness.
It's kind of like saying, hey, look guys--
we don't have to spend a lot of resources defending ourselves
right now against a specific infection.
Let's just do general barrier maintenance and make sure
we don't have problems in the future.
So that's the Th cells.
They not only downregulate excess responses, they're probably, like,
ensuring peacetime maintenance of your barriers.
Now they also probably provide some really serious opportunities
for therapeutic interventions.
If you have an autoimmune disease, then there's
a good chance you are not downregulating it properly.
If you have a malignancy, you're probably not
attacking it as you should.
And this is really sneaky, but there are both cancers and viral genomes that
can produce substances that recruit T regulatory cells.
And so, essentially, they're basically lying to your immune system,
or getting the T regulatory cells to lie to your immune system, and say, oh no,
boss-- this is no problem.
Leave it alone.
from being recruited when they shouldn't be,
that could also form the basis of a good therapy against cancer.
Now one of the things that we're going to look at
is a few reminders of how these different paracrine factors, ILs, will
interact with each other to produce various responses.
Here is a Th2 cell.
And this Th2 cell, then, will be coordinating a Th2 restrain response.
It does that, in part, by secreting IL-4.
IL-4 is a potent promoter of B cell proliferation.
And recall these are two cells that are very active in the Th2 response.
that acts on two different cells in somewhat different ways.
But in both cases, they're going to upregulate the proliferation.
Now here is sort of the opposite thing-- redundancy.
Here I've got my B cell proliferating.
And in this case I have a Th cell.
And it really could be 1 or 2, depending on the exact nature of the response.
But in this case, I'm probably after another Th2 response,
because I'm giving my cell IL-2-- very necessary for proliferation.
And I'm also giving it IL-4 and 5.
And either of those all by themselves will
cause the B cell to start dividing.
So there's a certain redundancy among these things.
That is, all three of these will lead to cell division in B cells.
Now there's also antagonism.
When we did that huge chart, remember there
were two systems where you could use one signal to get Th1 and 2 cells up
and running.
And the distinction between the two had to do
with signals that basically turned each other off.
We also saw that again with the decision to go either T17 or T reg,
where the retinoic acid and the IL-6 were mutually opposing each other.
And so let's go back to the original one.
Here is an antagonism response.
And so I didn't put the Th2 cell up here, but it is it secreting IL-4.
But in this case, clearly we've got some kind
of a viral or other serious infection.
Because the Th1 cell is secreting the IFN gamma.
And the IFN gamma is, in this case, acting on the B cell.
And it's going to be opposing the effect of the IL-4.
So while this B cell may not divide and produce quite as much antibody
as it would with a Th2 infection, it's still going to divide.
And in this case, it's going to class-switch into a different type.
So here we have the IgG3 secretion, and we're
going to then see that this will be opposed
by IL-4, which would have promoted the IgE.
And that's what we see here in synergy.
In this case, the Th2 cell is to creating
two of the factors, IL-4 and 5.
Either one by itself will make that B cell divide and proliferate.
But only when the two of them act together
do you get the class-switching to IgE.
So in this case, we're looking at a synergistic response, the synergy
being between the 4 and 5.
Both of them together have to be there to get the class switch to the IgE.
Now-- and it's not like you pull a switch on one of these guys
and you're done.
In most cases, you're going to have a continued ongoing conversation
between the various immune cells, particularly
between them and the Th cells.
Probably one of the most important conversations
you have is between the macrophages and the Th cells.
Recall these guys are going to be presenting antigen
and the macrophages are also-- here he is,
trying to phagocytise some hapless pathogen.
And when he does this, his toll-like receptors
are going to give him information on the pathogen.
And in this case, the macrophages decided it's a serious threat
and is producing IL-12.
All right.
So the IL-12 is upregulating a Th1 response, not a Th2.
And so when you have that Th1 response, you produce the IFN gamma.
And the interferon gamma, in turn, goes back and signals to the macrophages
that, yeah, you're right.
This is a serious problem.
And I want you to become more active.
I want you to become more active in phagocytosis
and I want you to become more active antigen presentation.
And I want some more B7 to help my buddies out
in order to make a proper response.
So you can see that I have to essentially oversimplify
things, looking at one thing at a time, because I've just
gone through five ways.
And you know what?
Those Th cells are doing all five things and more all at the same time.
And it is this kind of thing that makes it very difficult to figure out exactly
what's going on the immune system .
But we will also see it's this kind of thing that sometimes
gets disregulated, one way or the other.
And maybe you'll have a little bit more appreciation for all the opportunities
to go wrong.
And so having done that, let's go look at some disease-related responses,
in terms of what's happened with all of these signals.