Wednesday, February 21, 2007

Directing Cells: Vitamins instruct the Immune System

The topic I want to discuss today is the cues that T cells follow when they travel to various parts of the body. Normally, most T cells that are in the circulation do just that: they circulate. They go round and round the body following the bloodstream. But, there are a significant portion of T cells that reside in specific organs, organs that are not considered a part of the immune system per se, such as the skin, the liver and the intestine. Then how do these T cells decide to go to these organs, and then take up residence there? It appears to be a highly ordered process, during which T cells get specific signals that direct them to one organ or another. These directing signals also influence their function in their target organs and help specialize these T cells for their functions. T cells in the skin, for example, require the ability to react to different things than T cells in the intestine.

There are many molecules that can give T cells (or other cells, but I don't want to try to cover too many things at once) the guidance cues they need. One major class of molecules that do this are called chemokines and they do this by a process called chemotaxis. Chemotaxis is the movement of a cell in response to an increasing concentration of chemical, in this case a chemokine. Chemoattraction occurs when the movement is towards the higher concentration of the chemical. Chemokines are very small proteins that regulate cell homing, and are secreted by cells in specific organs. T cells that express the correct chemokine receptor then migrate to the organ where the chemokine is made. In particular, CCL27 is a chemokine made by skin cells, and CCR10 is the receptor on T cells that enables them to respond to CCL27.
CCR10 is not found on all T cells by default, it has to be induced or brought out on to the surface. A study in a recent issue of Nature Immunology (see below) finds that CCR10 can be brought to the surface of human T cells by the active form of Vitamin D.
In short, when T cells are exposed to the active form of Vitamin D, they start to express CCR10 on their surface. Previously activated T cells, that have already seen an antigen, are better that naive T cells at making CCR10 in response to active Vitamin D. Vitamin D is not active right off the blocks, it has to undergo three chemical modifications to become its final active form, called 1,25(OH)2D3. The first step is the conversion of an inactive precursor into Vitamin D3 by UVB rays if sunlight, this step occurs in the skin. Vitamin D3 is still not active. The second step is the conversion of Vitamin D3 into 25(OH)D3, in which form it can induce some CCR10 on T cells. The final step is the conversion into 1,25(OH)2D3, in which form it is most effective at inducing CCR10, and therefore migration to the skin.
The really cool thing about the paper is not only the idea that a vitamin can make T cells go to the skin, because that has been suggested before for vitamin A and the intestine (which I will come to in a minute). It is the demonstration that the T cells can themselves convert 25(OH)D3 into the active form to some extent, thereby making themselves able to migrate to the skin. even better, special antigen presenting cells called dendritic cells, can also do this, and can also accomplish the previous step, of converting Vitamin D3 into the 25 (OH)D3 form. The idea is then that dendritic cells activate T cells by presenting antigen to them, and while doing so also metabolize sunlight induced vitamin D3 and induce CCR10 expression on the T cells they are activating and therefore send them skinwards. The paper also shows that skin-derived dendritic cells are really good at converting vitamin D3 into the active form, and therefore can presumably induce better migration of T cells to the skin.
This is called "imprinting", and refers to the idea that T cells can be instructed by organ-specific cues to become organ-resident T cells. So, as an earlier study showed (see below), the vitamin A metabolite retinoic acid, is produced with greater efficiency by dendritic cells in the gut and induces T cells to home to the gut. Similarly, Vitamin D3 formed in the skin (Vitamin D2, the primary dietary form, is not as effective) can be metabolized by dendritic cells, presumably in the skin, and induces T cell homing to the skin. So cool! the organ itself "calls" T cells over, with whatever it has available.
This brings up so many things to think about, not the least of which is how much every system of the body is linked to the others. As a researcher, one tends to view one's own system in isolation, to study immunity alone or nutrition alone, whereas a truly healthy functional individual is the product of effective immunity and adequate nutrition. Superspecialization doesn't really seem to exist: one cell's vitamin is another cell's guidance cue.

Anyway, i though that was a nice study and a really nice idea, what do you think?

Papers referred to:

Sigmundsdottir H, Pan J et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. 2007. Nature Immunology Volume 8 pp285-293

Iwata M et al. Retinoic Acid Imprints Gut-Homing Specificity on T Cells. 2004. Immunity Volume 21 pp527-538


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