Trafficking and Homing – Lymphocyte Recirculation and Homing

00:01 Let’s now look at trafficking to mucosal tissues.

00:06 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.

00:16 But actually most pathogens are encountered via mucosal surfaces.

00:23 You may have a respiratory tract infection, you may have a gastrointestinal tract infection, you may have a sexually transmitted infection.

00:31 All of these types of pathogens are entering the body via mucosal surfaces.

00:36 So the immune system spends a lot of time and effort on protecting these very vulnerable mucosal tissues.

00:46 So in this particular example, we have a infection in the gut.

00:50 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.

01:10 Following their initial activation, those lymphocytes will migrate via the afferent lymphatics to the local mesenteric lymph nodes.

01:21 And there further activation will occur.

01:24 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.

01:36 Following their full activation, they will then proliferate and they will differentiate.

01:43 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.

02:03 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.

02:12 But those cells and molecules now need to go back to where the infection is.

02:16 It’s no good them being in the lymph node, they need to get back there.

02:20 So they do that via the lymphatic and blood circulations.

02:23 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.

02:33 You’ll also have cytotoxic T-lymphocytes and other cells that can help in the elimination of the pathogen.

02:43 As well as going back to the location where the stimulus was originally perceived, these lymphocytes can also travel to other mucosal tissues.

02:53 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.

03:08 Another very important location where pathogens can be encountered is of course the skin.

03:15 And therefore, there are also multiple mechanisms that facilitate the entry of lymphocytes into the skin.

03:24 In fact we have lots of immune system cells, both within the epidermis and the dermis of the skin.

03:31 Within the epidermis there are lots of dendritic cells that are specialized to detect antigens in these locations.

03:39 And this particular form of the dendritic cell is called a Langerhans cell.

03:43 So essentially a Langerhans cells is just a dendritic cell in the epidermis.

03:47 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.

03:55 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.

04:38 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.

04:48 And they know that because of molecules that we refer to as vascular adresins on the blood vessel endothelium at the particular location.

04:59 So by using adhesion molecules, the T-cells know exactly the location they need to home to.

05:08 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.

05:25 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.

05:42 So the molecules that those adhesion molecules recognize will be present on the blood vessel endothelium.

05:49 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.

06:37 Again, a different set of adhesion molecules.

06:40 Some of them are the same, some of them overlap.

06:42 So for example, you can see VLA-4 is present in each case.

06:48 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.

06:57 And it knows that because the ligands for those particular adhesion molecules are present on the blood vessel endothelium in the liver.

07:07 And the skin, as we’ve already mentioned is another important location that lymphocytes need to home back to.

07:13 So again there’s another combination code if you like, for lymphocytes that need to home to the skin.

07:21 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.

07:32 So for example, the molecule L-selectin which recognizes peripheral node adresin or PNAd on the endothelial cell.

07:41 The chemokine receptor CCR7 which recognizes both the CCL19 and the CCL21 chemokines.

07:53 The integrin family member, LFA-1 which is a β2-integrin which recognizes the molecule ICAM-1 on the endothelial cell.

08:05 All of these are adhesion molecules present on the surface of naïve T-cells.

08:10 However, following activation there are additional adhesion molecules that become expressed on the effector and the memory T-cells.

08:20 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.

08:32 CXCR3 which recognizes a number of different chemokines including CXCL10.

08:41 CCR5 which recognizes the chemokine CCL4 amongst others on the blood vessel endothelium.

08:49 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.