1,25-Dihydroxyvitamin D₃selectively and reversibly impairs T helper-cell CNS localization

Abstract

Pharmacologic targeting of T helper (T H ) cell trafficking poses an attractive opportunity for amelioration of autoimmune diseases such as multiple sclerosis (MS). MS risk is associated with vitamin D deficiency, and its bioactive form, 1,25-dihydroxyvitamin D3 [1,25(OH) 2 D 3 ], has been shown to prevent experimental autoimmune encephalomyelitis, a mouse model of MS, via an incompletely understood mechanism. Herein, we systematically examined 1,25 (OH) 2 D 3 effects on T H cells during their migration from the lymph nodes to the CNS. Our data demonstrate that myelin-reactive T H cells are successfully generated in the presence of 1,25(OH) 2 D 3 , secrete proinflammatory cytokines, and do not preferentially differentiate into suppressor T cells. These cells are able to leave the lymph node, enter the peripheral circulation, and migrate to the s. c. immunization sites. However, T H cells from 1,25(OH) 2 D 3 -treated mice are unable to enter the CNS parenchyma but are instead maintained in the periphery. Upon treatment cessation, mice rapidly develop experimental autoimmune encephalomyelitis, demonstrating that 1,25(OH) 2 D 3 prevents the disease only temporarily likely by halting T H cell migration into the CNS. The pathogeneses of MS and EAE require localization of selfreactive T cells to the CNS. Myelin-specific effector T cells are primed in the lymph nodes (LNs) and subsequently travel a complex route and arrive at the CNS barriers. There, a sequential interaction with a multitude of endothelial adhesion molecules and chemokines leads to T helper (T H ) cell migration into the CNS parenchyma. Several ligand/receptor pairs have been implicated in the pathogeneses of MS and EAE (5, 6). Therefore, manipulation of molecules involved in T-cell trafficking poses an attractive opportunity for therapeutic interventions. Recent studies have highlighted a role for vitamin D in immune cell migration (7-10), but whether 1,25(OH) 2 D 3 affects trafficking of lymphocytes in MS and/or EAE has not been investigated.A recent study using conditional deletion of the vitamin D receptor (VDR) has demonstrated that 1,25(OH) 2 D 3 prevents EAE by acting directly on the encephalitogenic T H cells (11 (Fig. S1), were recovered from the CNS of 1,25(OH) 2 D 3 -treated mice, all of which remained disease-free ( Fig. 1 A and B). Moreover, both vehicle-and 1,25(OH) 2 D 3 -treated groups had significantly higher proportions of splenic CD4 + T cells compared with the naive control (Fig. 1B). Thus, EAE prevention is accompanied by T H cell expansion in the periphery and a complete absence of inflammatory infiltrates in the CNS of 1,25(OH) 2 D 3 -treated animals, leading us to hypothesize that 1,25 (OH) 2 D 3 affects the ability of encephalitogenic T cells to enter the CNS without interfering with their activation.1,25(OH) 2 D 3 Does Not Affect Activation of Pathogenic T H Cells. We next examined the effect of 1,25(OH) 2 D 3 on the peripheral inflammatory response following immunization (Fig. S2). An equivalent increase in the proportion...

Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential

“…However, in this disease model, CD4 + T cells are likely the prime 1,25(OH) 2 D 3 target cells, since other studies show that in this model CD8 + T cells are dispensable for the effects of 1,25(OH) 2 D 3 (174). Further strengthening the hypothesis that the suppression of EAE by 1,25(OH) 2 D 3 is driven by modulation of CD4 + T cells, is the finding that 1,25(OH) 2 D 3 prevents CD4 + Th cell migration into the CNS (175). Finally, VDR binding is enriched near SNPs associated with autoimmune diseases in human CD4 + T cells, suggesting that these cells are also important in the effects of 1,25(OH) 2 D 3 in human autoimmunity (8).…”

Effects of Vitamin D treatment on thyroid autoimmunity

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