1,25-Dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization

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, TH 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.