1α,25-dihydroxyvitamin D3 restores thymocyte apoptosis sensitivity in non-obese diabetic (NOD) mice through dendritic cells

Aims/hypothesis: Resistance of NOD thymocytes to apoptosis-inducing signals is restored by 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-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 1 alpha,25(OH)(2)D-3. Methods and results: Female NOD mice were treated with 1 alpha,25(OH)(2)D-3 (5 mu g/kg/2d) from 21 to 70 days. Vehicle-treated NOD and NOR mice served as controls. Analysis of thymic T lymphocytes from 1 alpha,25(OH)(2)D-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 1 alpha,25(OH)(2)D-3-treated NOD mice had increased CD8 alpha(+)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 1 alpha,25(OH)(2)D-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 1 alpha,25(OH)(2)D-3- treated mice. Conclusion/interpretation: We conclude that 1 alpha,25(OH)(2)D-3 needs both thymic T cell- and dendritic cell-compartments to exert its apoptosis-restorative effects in NOD thymocytes. (c) 2005 Elsevier Ltd. All rights reserved.