1α,25-Dihydroxyvitamin D 3 restores thymocyte apoptosis sensitivity in non-obese diabetic (NOD) mice through dendritic cells

Abstract

Aims/hypothesis Resistance of NOD thymocytes to apoptosis-inducing signals is restored by 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2D 3), a therapy preventing diabetes in NOD mice. We studied whether modulation of thymocyte apoptosis is due to direct effects on thymic T lymphocytes or indirect effects via thymic dendritic cells, since both cell types constitute known targets for 1α,25(OH) 2D 3. Methods and results Female NOD mice were treated with 1α,25(OH) 2D 3 (5 μg/kg/2d) from 21 to 70 days. Vehicle-treated NOD and NOR mice served as controls. Analysis of thymic T lymphocytes from 1α,25(OH) 2D 3-treated mice revealed a decrease in number of apoptosis-resistant CD4 +CD8 + and CD4 +CD8 −HSA high T lymphocyte subsets, higher pro-apoptotic IL-2 and FasL, and lower anti-apoptotic Bclx-L mRNA expression levels. Thymic dendritic cells from 1α,25(OH) 2D 3-treated NOD mice had increased CD8α +FasL + and CD80 +/86 + expression compared to control NOD mice. In a syngeneic co-culture system of thymocytes and thymic dendritic cells, apoptosis levels were 20% higher only in co-cultures where both T cell- and dendritic cell-compartments originated from 1α,25(OH) 2D 3-treated mice. Activation-induced cell death-sensitivity in peripheral T lymphocytes was comparable to levels present in NOR mice, confirming better thymic selection in 1α,25(OH) 2D 3-treated mice. Conclusion/interpretation We conclude that 1α,25(OH) 2D 3 needs both thymic T cell- and dendritic cell-compartments to exert its apoptosis-restorative effects in NOD thymocytes.