Vitamin D, invariant natural killer T-cells and experimental autoimmune disease

Abstract

Vitamin D is an important regulator of the immune system in general and multiple sclerosis in particular. Experimentally (i), invariant natural killer T (iNKT) cells have been shown to be important suppressors of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE; an animal model of multiple sclerosis). Conversely, in experimental allergic asthma iNKT cells are required for disease induction and are therefore pathogenic. The active form of vitamin D (calcitriol) suppresses EAE. The development of EAE symptoms is accelerated in vitamin D deficiency. Interestingly experimental asthma is less severe in vitamin D deficiency although there is no effect of calcitriol on disease severity. The data suggest that an important target of vitamin D in EAE and asthma are the iNKT cells. Vitamin D and/or vitamin D receptor deficiency results in the impaired development of iNKT cells. Vitamin D is critical very early during development of the immune system. Low levels of vitamin D in utero resulted in significantly reduced numbers of iNKT cells that failed to recover when calcitriol was used to supplement neonatal or adult mice. The data suggest that one of the consequences of early vitamin D deficiency is a reduction in the numbers of iNKT cells that develop. The iNKT cells are required for the beneficial effects of calcitriol in EAE. The important role of vitamin D on iNKT cells could impact the development of human immune-mediated diseases including multiple sclerosis and asthma.

Fig. 1

(Colour online) Vitamin D and vitamin D receptor (VDR) targets in invariant natural killer T (iNKT) cell development^(13,16). iNKT cells develop in the thymus following several different phenotypic changes. The earliest iNKT cell precursor, DP^dim expresses the invariant T-cell receptor (tetramer⁺) and CD24⁺. The early iNKT cells down-regulate CD24 and diverge from the other CD4/CD8 DP cells that go on to become conventional T-cells. Expression of two transcription factors (Fyn and NF-κB) is important in the movement of iNKT cells from stage (S) 0 to S1. Vitamin D and VDR deficiency affect the number of iNKT cells that rapidly expand and enter the S1 stage in maturation. There is no effect of vitamin D deficiency on the further maturation of iNKT cells. VDR knockout (KO) iNKT cells have an additional block in maturation at the S2 stage and fail to fully develop into mature iNKT cells. T-bet and NF-κB expression is associated with the transition of iNKT cells from S2 to S3. VDR KO iNKT cells express significantly less T-bet than there fully mature S3 wild-type counterparts⁽¹⁶⁾.

Fig. 2

(Colour online) Gestational effects of vitamin D deficiency on invariant natural killer T (iNKT) cells⁽¹³⁾. Vitamin D-sufficient, vitamin D-deficient or calcitriol-supplemented diets were fed to mice during three different windows of time: pregnancy, lactation (0–3 weeks), following weaning (3–8 weeks of age). The vitamin D-sufficient or calcitriol-treated throughout mice had the highest numbers of iNKT cells. Vitamin D-deficient throughout or switching to D sufficient diets from 3 to 8 weeks had the fewest iNKT cells. Supplementing D-deficient mice with calcitriol from 3 to 8 weeks or during lactation until 8 weeks increased iNKT cell numbers somewhat but not to the level found in the vitamin D-sufficient mice.