Let us begin with a discussion of the fates and functions of CD4 Th cells.
The naïve CD4 T cell is a rather remarkable cell.
It is basically a nucleus with the barest rim of cytoplasm.
Yet within it is the potentiality to achieve a series of distinct
differentiated states that we have known about over the last 20-25 years,
when the distinction between Th1 and Th2 cells was first realized.
We know that Th1 cells have, as their principal function,
the dealing with intracellular pathogens,
and that when they are dysregulated,
they can be responsible for much tissue-specific autoimmunity.
Th2 cells, my personal favorites,
have an important role to play in protection against extracellular parasites,
and when they are dysregulated,
they result in allergic inflammatory disorders.
More recently defined are the Th17 cells.
They are important in providing protection against extracellular bacteria and fungi.
They too, when dysregulated,
cooperate a good deal with Th1 cells in mediating organ-specific autoimmunity.
Finally, the induced or iT regulatory cells,
which together with their congeners,
the natural T regulatory cells,
play a critical role in immune tolerance and lymphocyte homeostasis.
What defines the distinctive functionalities
of these distinctive cell types are two features.
One, the suite of cytokines that they produce,
and secondly, the chemokine receptors that they express.
The former causing their effective functions,
and the latter allowing them to be directed to the sites
where they will mediate their functionality.
Each of the four different cell types mediates or produces a signature cytokine.
For Th1 cells,
that is interferon-gamma (IFN-γ).
For Th2s, again my personal favorite, it is interleukin-4 (IL-4).
For Th17s, it would be IL-17a,
and finally for iTregs it will probably be TGF-β,
although this would still be a matter of some uncertainty.
One of the most attractive features of the study of this set of differentiated cells,
is the fact that we understand with great precision
how to carry out this differentiation in vitro.
This has two very important effects.
One, it allows us to understand, in very considerable detail,
the distinctive molecular events involved in the differentiation process.
Secondly, because the initiating cells can be
obtained in very large numbers and in highly purified form,
and we understand their biology with a great deal of precision,
it presents itself as one of the very best mammalian systems in which we study differentiation.
The process of a naïve CD4 T cell differentiating to the four distinctive types,
firstly involves the engagement of the T cell receptor with its cognate antigen,
and secondly, involves the establishment of a particular cytokine milieu.
In general, two critical cytokines are involved.
For Th1 cells,
that is IFN-γ plus IL-12,
for Th2 cells its IL-4 plus IL-2.
For Th17 cells it is TGF-β plus IL-6 or IL-21.
Finally, for iTreg, it is TGF-β plus IL-2.
One of the very interesting effects that should be noted for Th1,
Th2s and to a lesser degree, Th17 cells,
is that one of the major products of those cells,
Th1's IFN-γ, Th2's IL-4,
is one of the critical inducers.
This is a little more indirect for Th17s in which one generally uses
IL-6 for differentiation purposes, and the cell type produces IL-21,
which can then substitute for IL-6.
But it suggests, as I will discuss later,
the possibility of a very important positive feedback loop in the process of differentiation.
In closing this opening discussion,
I want to point out that we also know the critical transcription factors which underlie
the production of the cytokines that each of
these four cell populations make and that determine the functionalities of these cell.
In each case, there is what is referred to as
a master regulatory transcription factor.
For Th1s that is T-bet,
for Th2s GATA-3,
for TH17s RORγt,
and for induced T regulatory cells Foxp3.
In addition, each of the differentiation processes involve
the use of a cytokine that activates a particular stacked molecule.
Again, for Th1 cells, that is Stat4,
which is of course activated by IL-12,
for Th2 cells it is Stat5 activated by IL-2.
For Th17 cells it is Stat3 activated by IL-6 or IL-21,
and for iTregs, it would be Stat5,
also activated by IL-2.
This gives us a picture of some of
the interesting properties of these very important cell types.
Now, I must also say, that this presentation,
this initial slide, represents somewhat of an oversimplification.
The question of whether the four cell populations I've
described are in fact complete can be discussed in detail.
In fact, almost certainly there are more.
There are the so-called T follicular helper cells,
which are achieving a great deal of prominence.
There are what may be subsets of other populations,
for example, Th9 cells,
which appear to be closely related to Th2 cells,
Th22 cells, which may be closely related to Th17 cells and possibly other cell types.
But the principles that underlie
the differentiation and behavior of these cells, I think,
is well illustrated by our concentration on these particular cell types.
New technology now allows