Vitamin D crucial to activating immune defenses Mar 2010
March 7, 2010 Vitamin D crucial to activating immune defenses
From http://www.physorg.com/news187187075.html 
T lymphoycte cell (small cell with red surface) scanning another cell for the presence of foreign molecules. Credit: Professor Carsten Geisler

Scientists at the University of Copenhagen have discovered that Vitamin D is crucial to activating our immune defenses and that without sufficient intake of the vitamin, the killer cells of the immune system - T cells - will not be able to react to and fight off serious infections in the body.
For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be 'triggered' into action and 'transform' from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen.
The researchers found that the T cells rely on vitamin D in order to activate and they would remain dormant, 'naďve' to the possibility of threat if vitamin D is lacking in the blood.
Chemical Reaction that Enables Activation
In order for the specialized immune cells (T cells) to protect the body from dangerous viruses or bacteria, the T cells must first be exposed to traces of the foreign pathogen. This occurs when they are presented by other immune cells in the body (known as macrophages) with suspicious 'cell fragments' or 'traces' of the pathogen. The T cells then bind to the fragment and divide and multiply into hundreds of identical cells that are all focused on the same pathogen type. The sequence of chemical changes that the T cells undergo enables them to both be 'sensitized to' and able to deliver a targeted immune response.
Professor Carsten Geisler from the Department of International Health, Immunology and Microbiology explains that "when a T cell is exposed to a foreign pathogen, it extends a signaling device or 'antenna' known as a vitamin D receptor, with which it searches for vitamin D. This means that the T cell must have vitamin D or activation of the cell will cease. If the T cells cannot find enough vitamin D in the blood, they won't even begin to mobilize. "
T cells that are successfully activated transform into one of two types of immune cell. They either become killer cells that will attack and destroy all cells carrying traces of a foreign pathogen or they become helper cells that assist the immune system in acquiring "memory". The helper cells send messages to the immune system, passing on knowledge about the pathogen so that the immune system can recognize and remember it at their next encounter. T cells form part of the adaptive immune system, which means that they function by teaching the immune system to recognize and adapt to constantly changing threats.
Vitamin D crucial to activating immune defenses

When the naďve T cell recognizes foreign molecules with its T cell receptor (TCR) it sends activation signals (1) to the VDR gene. The VDR gene now starts the production of VDR (2). VDR binds vitamin D in the T cell (3) and becomes activated. Vitamin D bound to activated VDR goes back into the cell nucleus and activates the gene for PLC-gamma1 (5). PLC-gamma1 is produced (6) and the T cells can get started. Credit: Professor of Immunology, Carsten Geisler
Activating and Deactivating the Immune System
For the research team, identifying the role of vitamin D in the activation of T cells has been a major breakthrough. "Scientists have known for a long time that vitamin D is important for calcium absorption and the vitamin has also been implicated in diseases such as cancer and multiple sclerosis, but what we didn't realize is how crucial vitamin D is for actually activating the immune system - which we know now. "
The discovery, the scientists believe, provides much needed information about the immune system and will help them regulate the immune response. This is important not only in fighting disease but also in dealing with anti-immune reactions of the body and the rejection of transplanted organs. Active T cells multiply at an explosive rate and can create an inflammatory environment with serious consequences for the body. After organ transplants, e.g. T cells can attack the donor organ as a "foreign invader". In autoimmune disease, hypersensitive T cells mistake fragments of the body's own cells for foreign pathogens, leading to the body launching an attack upon itself.
The research team was also able to track the biochemical sequence of the transformation of an inactive T cell to an active cell, and thus would be able to intervene at several points to modulate the immune response. Inactive or 'naďve' T cells crucially contain neither the vitamin D receptor nor a specific molecule (PLC-gamma1) that would enable the cell to deliver an antigen specific response.
The findings, continues Professor Geisler "could help us to combat infectious diseases and global epidemics. They will be of particular use when developing new vaccines, which work precisely on the basis of both training our immune systems to react and suppressing the body's natural defenses in situations where this is important - as is the case with organ transplants and autoimmune disease."

Most Vitamin D is produced as a natural byproduct of the skin's exposure to sunlight. It can also be found in fish liver oil, eggs and fatty fish such as salmon, herring and mackerel or taken as a dietary supplement. No definitive studies have been carried out for the optimal daily dosage of vitamin D but as a large proportion of the population have very low concentrations of vitamin D in the blood, a number of experts recommend between 25-50mg micrograms a day.
More information: The findings will be published in the latest edition of Nature Immunology, (Vitamin D controls T cell antigen receptor signaling and activation of human T cells ) on March 7 - DOI:10.1038/ni.1851
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Abstract 
Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-γ1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering led to an upregulation of ~75-fold in PLC-γ1 expression, which correlated with greater TCR responsiveness. Induction of PLC-γ1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-γ1, which are required for subsequent classical TCR signaling and T cell activation. 
Figures captions? 
Figure 1: Lower sensitivity of naive T cells to TCR triggering. 
() TCR expression in naive and primed T cells after stimulation with beads coated with anti-CD3 and anti-CD28 (cell/bead ratio, above graphs), presented relative to that of untreated cells. Data are from five independent experiments (error bars, s.d.). 
() Immunoblot analysis of tyrosine phosphorylation (pY) and expression of Zap70, Lat, Erk and TCRζ (loading control) in naive and primed T cells stimulated for 0–10 min with beads coated with anti-CD3 and anti-CD28. Each vertically aligned lane represents the same cell sample. Data are representative of three independent experiments. 
() Calcium flux in naive and primed T cells left unstimulated (Medium) or stimulated at 30 s with a mixture of antibody to CD3 (anti-CD3) and anti-CD28, with ionomycin added at 465 s. Results are for gated CD8+ T cells; CD4+ T cells produced the same results. Data are representative of three independent experiments. * 
Figure 2: Phosphorylation and expression of PLC-γ1 in naive and primed T cells. 
() Immunoblot analysis of tyrosine phosphorylation and expression of PLC-γ1 and TCRζ (loading control) in naive and primed T cells stimulated for 0–10 min with beads coated with anti-CD3 and anti-CD28 (cell/bead ratio, 1:3).
 () RNA-hybridization analysis of the expression of PLC-γ1 mRNA and 28S rRNA (loading control) in T cells stimulated for 0–9 d. () Quantification of PLC-γ1 mRNA expression during differentiation, normalized to the loading control and presented (per T cell) relative to basal expression in naive T cells. 
() Immunoblot analysis of the expression of PLC-γ1, TCRζ (loading control) and Glut1 (activation marker22) in T cells stimulated for 0–9 d. 
() Quantification of PLC-γ1 expression during differentiation, normalized to the loading control and presented (per T cell) relative to basal expression in naive T cells. Data are representative of three separate experiments (,,) or are from three experiments (,; error bars, s.d.). * 
Figure 3: VDR induction precedes PLC-γ1 upregulation. () Immunoblot analysis of VDR, PLC-γ1 and TCRζ (loading control) in the cytoplasmic and nuclear fractions of T cells stimulated for 0–3 d with beads coated with anti-CD3 and anti-CD28 (cell/bead ratio, 1:3). 
() Immunoblot analysis of the expression of VDR, PLC-γ1 and TCRζ in purified naive and primed CD4+ and CD8+ T cells. 
() Immunoblot analysis of the expression of VDR, PLC-γ1 and TCRζ in T cells stimulated for 3 d in the presence of the VDR antagonists ZK191784 and ZK203278 (concentration, above lanes). 
() Flow cytometry of naive T cells (far left, top row) and T cells stimulated for 3 d in the presence of various concentrations (above plots) of ZK191784 (other plots, top row) or ZK203278 (bottom row). Numbers adjacent to outlined areas indicate percent cells in each. SSC, side scatter; FSC, forward scatter. 
() CFSE profiles of naive T cells (top row; gray filled histogram) and primed T cells stimulated for 3 d without further additions (black lines) or in the presence of vehicle (middle; gray filled histogram) or ZK191784 (bottom row; gray filled histogram). 
() Immunoblot analysis of the expression of VDR, PLC-γ1 and TCRζ in T cells stimulated for 3 d in the presence of ketoconazole (0 or 1 μg/ml) and either 25(OH)D3 (25; 0.5 μM) or 1,25(OH)2D3 (1,25; 0.5 μM). 
() Proliferation index of T cells from patients with chronic deficiency of 25(OH)D3 and 1,25(OH)2D3 and controls with normal serum concentration of 25(OH)D3 and 1,25(OH)2D3, stimulated for 3 d. 
() Concentration of 25(OH)D3 (left vertical axis; open circles) and 1,25(OH)2D3 (right vertical axis; filled circles) in patient and control sera. Each symbol represents an individual serum sample; small horizontal lines indicate the mean. Data are representative of three separate experiments. * 

Figure 4: The alternative TCR signaling pathway induces VDR expression. 
() Immunoblot analysis of Thr180 phosphorylation (pT) and expression of p38 and TCRζ (loading control) in naive and primed T cells stimulated for 0–10 min with beads coated with anti-CD3 and anti-CD28 (cell/bead ratio, 1:3). 
() Immunoblot analysis of the expression of VDR, PLC-γ1 and GAPDH (glyceraldehyde phosphate dehydrogenase; loading control) in E6-1 (E6) and J.gamma1 (Jγ1) cells stimulated for 24 h with anti-CD3 and anti-CD28. 
() Immunoblot analysis of Thr180 phosphorylation and expression of p38 in unstimulated naive T cells and in naive T cells stimulated for 30 min with magnetic beads coated with anti-CD3 and anti-CD28 (cell/bead ratio, 1:3) in the presence or absence of the p38 inhibitor SB203580 (concentration, above lanes). 
() Immunoblot analysis of the expression of VDR, PLC-γ1 and TCRζ in T cells stimulated for 3 d in the presence or absence of SB203580 (concentration, above lanes). 
() Flow cytometry of T cells stimulated for 3 d in the presence or absence of SB203580 (concentration, above plots). Numbers adjacent to outlined areas indicate percent cells in each. 
() CFSE profiles of primed T cells stimulated for 3 d with beads coated with anti-CD3 and anti-CD28 (black line) or beads plus 10 μM SB203580 (gray filled histogram). 
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Some comments from DIGG
      +52 diggs +54 / -2       happyseamonsterhappyseamonster         on 03/10/2010
      Security guru Steve Gibson has lots of good info here: http://www.grc.com/health/vitamin-d.htm
      +25 diggs +31 / -6       pika2000pika2000       on 03/10/2010
      Kinda late. I jumped into the Vit D bandwagon after listening to Steve Gibson in the Security Now Podcast. The "stay in the sun" thing doesn't do much anymore. A lot, if not majority of people just cannot produce enough vit D just from sun exposure alone. The only problem is, our body don't have the capability to prevent overdosing when taking oral vit D. So if you want to play it safe, just do 1000-2000IU per day, or 5000IU every 3 days, and check with your MD.
      Kemp34kemp34       on 03/10/2010
      Also, the darker your complexion, the more likely you are to be deficient in vitamin D.
      http://www.associatedcontent.com/article/2213949/a ...
      I lot of American health issues appear to be more acute in folks with darker skin, and the reduced amount of vitamin D they get from the sun may be a cause.
      Most American children are vitamin D deficient as well:
      http://www.cnn.com/2009/HEALTH/08/03/vitamin.d.chi ...
      Morals of the story: most people could probably use a boost of vitamin D for their immune systems and long run health, especially those with darker skin. When you hear about flu scares, you should boost intake of key vitamins. Finally, the CDC should not be such a pharma tool, and should actually let people know about other basic steps they can take to avoid illness, such as getting tested for vitamin D levels and increasing intake as needed.
      Lordmikelordmike       on 03/10/2010
      That would be incorrect. The FDA recently changed their deficiency guidelines, and anyone who has serum levels under 30mmol/L is deficient. At levels under 30, the parathyroid glands activate trying to increase serum calcium by leeching them from your bones and also excreting too much phosphorous.
      Most people who live in cold weather climates are deficient. This deficiency is exacerbated by the increased use of sunscreen. Even in Australia, rickets is making a comeback 'cos of all the sunscreen use.
      Dr. Weil has increased his recommended dose for people to 2,000 IU's a day. Just drinking milk simply won't give you enough vitamin D.
      FrostekFrostek       on 03/10/2010
      Apparently cholesterol is a precursor for vitamin D, but since we all cut back on it, there's less