1alpha,25-dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis

Abstract

Epidemiological evidence indicates that the vitamin D status after birth modulates the risk for development of type 1 diabetes mellitus (T1DM). We previously demonstrated that the biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), as well as its analogue TX527 permanently alter the morphology and T cell stimulatory function of human dendritic cells (DC). Here, we studied the mechanism of T cell modulation by 1,25(OH)2D3 or analogue treated DC. By using CFSE-labelled autoreactive T cells, we observed that T cell proliferation is hampered upon coculture with modulated DCs, i.e. T cells underwent fewer cycles of cell divisions when compared to T cells stimulated by nontreated DCs. Moreover, 1,25(OH)2D3 or analogue modulated DCs induced significantly higher numbers of early apoptotic (annexin V+/PI-) and/or late apoptotic (annexin V+/PI+) T cells. Apoptosis was selectively induced in T cells activated by modulated DC, since other T cells present in the same cultures, either resting or activated by control untreated DC, were unaffected. Thus, in vitro preconditioning of DC with 1,25(OH)2D3 or analogue yields regulatory DC that may interfere with ongoing autoimmunity in vivo without affecting T cells with other specificities.