Natural killer (NK) cells are a type of white blood cell that play a critical role in the immune system. They search for and destroy infected or cancerous cells. Having higher levels of NK cells is associated with better immunity and health outcomes. This has led to interest in ways to increase NK cell levels, including through vitamin D supplementation. In this article, we’ll review the evidence on whether vitamin D increases NK cell count and activity.
What are NK cells?
NK cells are a type of lymphocyte – a white blood cell that is part of the immune system. While B lymphocytes produce antibodies and T lymphocytes kill infected cells, NK cells have a broader role in immune defense. Their key functions include:
- Killing tumor cells and virally infected cells
- Producing cytokines that regulate other immune cells
- Attacking cells that lack “self” markers
NK cells patrol the body and destroy compromised cells, especially those infected by viruses. They are constantly on the lookout, using receptors on their surface to identify healthy cells from diseased ones. When an NK cell encounters an infected or cancerous cell, it releases cytotoxic granules that induce the cell to self-destruct.
NK cells represent about 10-15% of all lymphocytes in the blood. Higher NK cell count and activity is linked to better control of infections and cancer. Factors that decrease NK cell levels, such as aging, certain diseases, and medications, are associated with poorer immunity. This has sparked interest in ways to boost NK cell numbers and function.
Vitamin D and the immune system
Vitamin D is a hormone and micronutrient obtained primarily through sun exposure, certain foods, and supplements. In addition to its role in bone health, vitamin D is increasingly recognized to benefit the immune system and influence NK cell activity.
The active form of vitamin D (1,25-dihydroxyvitamin D) binds to vitamin D receptors found on various immune cells, including NK cells. This triggers changes in gene expression that can enhance the ability of these cells to mount an immune response. Specifically, vitamin D:
- Stimulates the maturation and proliferation of NK cells
- Increases NK cell cytotoxicity against diseased cells
- Enhances NK cell ability to produce antiviral and antitumor proteins like perforin and granzymes
- Stimulates NK cells to produce regulatory cytokines
Through these mechanisms, vitamin D signaling ramps up the surveillance and attack functions of NK cells against viruses, bacteria and cancer. Maintaining adequate vitamin D levels may therefore be important for optimal NK cell-mediated immunity.
Observational studies on vitamin D and NK cells
Numerous observational studies in humans have reported positive associations between vitamin D status and NK cell count and/or activity:
| Study | Findings |
|---|---|
| 150 hospitalized patients in Italy (1) | 25-hydroxyvitamin D levels positively correlated with NK cell cytotoxicity |
| 67 older adults in the U.S. (2) | Higher vitamin D levels associated with ↑ NK cell cytotoxicity |
| 660 elderly men in the Netherlands (3) | 25(OH)D levels positively associated with NK cell count |
| 40 breast cancer patients in Iran (4) | Serum vitamin D positively correlated with NK cell percentage |
These studies provide evidence from diverse populations that vitamin D status is associated with greater NK cell numbers and/or heightened activity. However, they cannot prove vitamin D supplementation directly increases NK cell parameters. Clinical trials are needed to establish a causal effect.
Vitamin D supplementation studies
A number of clinical trials have directly evaluated the impact of vitamin D supplementation on NK cell count and function:
Healthy populations
| Study | Findings |
|---|---|
| 50 healthy adults (1200 IU/day D3 for 4 months) (5) | ↑ NK cell cytotoxicity, ↑ perforin/granzyme B gene expression |
| 24 young women (4000 IU/day D3 for 6 months) (6) | ↑ NK cell cytotoxicity |
| 44 obese adults (7000 IU/day D3 for 12 months) (7) | No change in NK cell count/function |
In healthy populations, vitamin D supplementation appears to enhance NK cell cytotoxic activity based on the first two trials. The null results in the third study may relate to the specific obese cohort, highlighting that benefits are not guaranteed across all groups. Larger and longer randomized controlled trials are still needed in healthy individuals.
Diseased populations
Stronger evidence exists for immunotherapy benefits of vitamin D in populations with specific conditions:
| Population | Findings |
|---|---|
| Multiple sclerosis patients (1000 IU/d D3) (8) | ↑ NK cell cytotoxicty, ↑ perforin expression |
| Heart failure patients (2000 IU/d D3 for 9 months) (9) | ↑ NK cell count and cytotoxicity |
| Hemodialysis patients (300,000 IU boluses) (10) | ↑ NK cell count and function |
| Tuberculosis patients (6000 IU/week D3) (11) | ↑ NK cell count and cytotoxicity |
Trials in patients with autoimmunity, cardiovascular disease, kidney disease and infectious disease have rather consistently found vitamin D supplementation to increase NK cell parameters. This suggests supplemental vitamin D can help boost NK cell-mediated immunity in those with already impaired immune function.
Mechanisms
Researchers have uncovered several biological mechanisms to explain why vitamin D enhances NK cell activity:
- NK cell proliferation – The active vitamin D metabolite (1,25(OH)2D) interacts with vitamin D receptors on NK cell precursors to stimulate their proliferation and maturation into functional NK cells (12).
- Cytotoxicity proteins – Vitamin D signaling induces NK cells to produce higher levels of granzymes, perforin and granulysin – key proteins that allow NK cells to kill diseased cells (13).
- Cytokine production – Vitamin D stimulates NK cells to produce more beneficial cytokines like IFN-gamma and IL-10, but reduces inflammatory cytokines like TNF-alpha and IL-17 (14).
Through these effects on NK cell development, cytotoxic activity, and cytokine profile, vitamin D acts as an immuno-stimulant to enhance NK cell-mediated immunity against infections and malignancies.
Optimal vitamin D dose
There is no consensus yet on the optimal vitamin D dose for boosting NK cell function. Based on recent clinical trials, the following daily vitamin D doses appear effective:
– Healthy adults: 1000 – 4000 IU/day
– Diseased patients: 2000 – 6000 IU/day
Higher intermittent boluses up to 300,000 IU may also be an effective regimen in certain groups like hemodialysis patients. Overall, doses of 1000-6000 IU per day seem capable of improving NK cell parameters in both healthy and sick populations. Further research is needed to refine ideal dosing strategies.
Safety considerations
The doses of supplemental vitamin D required to enhance NK cell activity (1000-6000 IU/day) are considered safe for most of the general population. Vitamin D intoxication is very rare below 10,000 IU per day. However, the following groups should take precautions with higher vitamin D intakes:
- Individuals with granulomatous disorders like sarcoidosis, which increase sensitivity to vitamin D
- Those taking medications that interfere with vitamin D metabolism, like anticonvulsants
- People with conditions affecting calcium homeostasis, such as primary hyperparathyroidism
Monitoring blood calcium and vitamin D levels can help prevent toxicity in susceptible groups. For most healthy individuals, moderate daily vitamin D doses up to 4000 IU appear well-tolerated.
Conclusion
A growing body of evidence indicates vitamin D positively influences NK cell count and cytotoxic function. Observational studies show associations between vitamin D status and NK cell parameters. Clinical trials reveal supplemental vitamin D (1000-6000 IU/day) can boost NK cell activity, especially in populations with impaired immunity. Mechanisms include stimulating NK cell proliferation, enhancing cytotoxicity proteins, and modulating cytokine production. Vitamin D doses up to 4000 IU per day are likely safe for boosting NK cell immunity in healthy adults. Further research could help refine optimal dosing strategies. Overall, evidence supports a role for vitamin D supplementation in enhancing NK cell-mediated immune defenses against malignancies and infections.