Let’s now look at trafficking
to mucosal tissues.
Remember, and it’s always really worth remembering
this, where do we first encounter pathogens?
You may have an abrasion
on the skin for example.
But actually most pathogens are
encountered via mucosal surfaces.
You may have a respiratory tract infection,
you may have a gastrointestinal
tract infection, you may have a sexually transmitted infection.
All of these types of pathogens are
entering the body via mucosal surfaces.
So the immune system spends a lot of time and effort
on protecting these very vulnerable mucosal tissues.
So in this particular example,
we have a infection in the gut.
So there is some pathogenic bacteria here in the gut and they
are going to invade, and in the Peyer’s patches of the lamina
propria, there will be an initiation of an immune response
involving the lymphocytes that are present in that location.
Following their initial activation,
those lymphocytes will migrate
via the afferent lymphatics to the local mesenteric lymph nodes.
And there further
activation will occur.
So there’s some preliminary activation within
the Peyer’s patch, but then subsequently to
get full activation of these lymphocytes, they
need to move to the mesenteric lymph nodes.
Following their full activation, they will
then proliferate and they will differentiate.
And subsequently they will leave the mesenteric lymph nodes and
travel via the efferent lymphatics, eventually via the thoracic
duct rejoining the blood circulation
and going back to the lamina
propria, which is where the infection was originally located.
You have a gastrointestinal tract infection,
you’re activating lymphocytes in the
GI tract, you’re super-activating them if
you’d like in the mesenteric lymph nodes.
But those cells and molecules now need
to go back to where the infection is.
It’s no good them being in the lymph
node, they need to get back there.
So they do that via the lymphatic
and blood circulations.
And you’ll have a dimeric secretory IgA,
which is very important in protecting mucosal
surfaces; that will be produced by plasma
cells that have gone back to the gut.
You’ll also have cytotoxic T-lymphocytes and other
cells that can help in the elimination of the pathogen.
As well as going back to the location
where the stimulus was originally
perceived, these lymphocytes can also
travel to other mucosal tissues.
And sometimes we talk about a common
mucosal immune system that cells activated
in one mucosal location can actually
home back to other mucosal locations.
Another very important location where pathogens
can be encountered is of course the skin.
And therefore, there are also multiple mechanisms that
facilitate the entry of lymphocytes into the skin.
In fact we have lots of immune system cells, both
within the epidermis and the dermis of the skin.
Within the epidermis there are lots of dendritic cells
that are specialized to detect antigens in these locations.
And this particular form of the dendritic
cell is called a Langerhans cell.
So essentially a Langerhans cells is
just a dendritic cell in the epidermis.
You’ll also have various types of
T-cells; one’s with both an alpha (α) beta
(β) T-cell receptor, and others with a
gamma (γ) delta (δ) T-cell receptor.
You never have T-cells with both
types of receptor, but there’ll
be some αβ T-cells and there’ll also be some γδ T-cells.
And likewise within the dermis
there’ll be αβ T-cells and also some
γδ T-cells, as well as dendritic
cells, natural killer cells,
macrophages and mast cells; so all
the kinds of cells that you need
to develop inflammatory responses
and specific adaptive responses.
And the lymphocytes in particular will
have arrived via the blood vessels using
these homing molecules that we’ve been
mentioning with the assistance of chemokines.
And following activation in the skin,
they can leave via the lymphatic
drainage and become activated in local draining lymph nodes.
So how do these lymphocytes actually
know where they need to go?
Do they know that they have to go to the
gut, or that they have to go to the skin?
Well yes, they do know that.
And they know that because of
molecules that we refer to as vascular
adresins on the blood vessel endothelium
at the particular location.
So by using adhesion molecules, the T-cells
know exactly the location they need to home to.
So looking at this particular example you
have in front of you now; this lymphocyte has
on its cell surface the adhesion molecules
L-selectin, VLA-4, LFA-1, LPAM-1 and CCR9.
And those particular molecules will tell the lymphocyte that it
needs to go to the gut, because on
the blood vessels in the gut, on
the surface of the endothelium,
there are the co-receptors if you
like, or the receptors for those particular adhesion molecules.
So the molecules that those adhesion molecules recognize
will be present on the blood vessel endothelium.
And these lymphocytes will be travelling through the blood
vessel, they would carry on on their journey, but when they get
to that particular location, they can see that the blood vessels
have on their surface, molecules that they can recognize.
So they will stop, and they will exit
the blood vessel and travel to the gut.
But what about if there’s
an infection in the lung?
You don’t want the lymphocytes when they exit the lymph
node to go to the gut if the infection is in the lung.
So as we can see here, lymphocytes that need to go
back to the lung, or to go to the lung following
activation in lymph nodes, they have a different
set of adhesion molecules on their surface.
And the receptors for those adhesion molecules will
be present just on the blood vessels within the lung.
Same thing for the liver.
Again, a different set
of adhesion molecules.
Some of them are the same,
some of them overlap.
So for example, you can see
VLA-4 is present in each case.
But there are some that are unique, and
the combination is a unique combination
telling that particular lymphocyte
that it needs to go to the liver.
And it knows that because the ligands
for those particular adhesion
molecules are present on the blood
vessel endothelium in the liver.
And the skin, as we’ve already mentioned is another
important location that lymphocytes need to home back to.
So again there’s another combination code if you
like, for lymphocytes that need to home to the skin.
So now just looking at a few of these
T-cell homing receptors, some of them are
present on T-cells before they become
activated, in other words, on naïve T-cells.
So for example, the molecule L-selectin which recognizes
peripheral node adresin or PNAd on the endothelial cell.
The chemokine receptor CCR7 which recognizes
both the CCL19 and the CCL21 chemokines.
The integrin family member, LFA-1 which is a β2-integrin
which recognizes the molecule ICAM-1 on the endothelial cell.
All of these are adhesion molecules
present on the surface of naïve T-cells.
However, following activation there
are additional adhesion molecules
that become expressed on the effector and the memory T-cells.
So for example, E- and P-selectin
ligand, which as the name suggests
bind to E- and P-selectins on the
blood vessel endothelial cells.
CXCR3 which recognizes a number of
different chemokines including CXCL10.
CCR5 which recognizes the chemokine CCL4
amongst others on the blood vessel endothelium.
And the integrins LFA-1 which is a β2-integrin,
and VLA-4 which is a β1-integrin,
which recognize ICAM-1 or VCAM-1 respectively
on the blood vessel endothelium.