Mesenchymal stem cells control alloreactive CD8⁺ CD28⁻ T cells.

CD28/ B7 co-stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients. However, cells lacking CD28 are not susceptible to belatacept treatment. As CD8+ CD28− T-cells have cytotoxic and pathogenic properties, we investigated whether mesenchymal stem cells ( MSC) are effective in controlling these cells. In mixed lymphocyte reactions ( MLR), MSC and belatacept inhibited peripheral blood mononuclear cell ( PBMC) proliferation in a dose-dependent manner. MSC at MSC/effector cell ratios of 1:160 and 1:2·5 reduced proliferation by 38·8 and 92·2%, respectively. Belatacept concentrations of 0·1 μg/ml and 10 μg/ml suppressed proliferation by 20·7 and 80·6%, respectively. Both treatments in combination did not inhibit each other's function. Allostimulated CD8+ CD28− T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B, interferon ( IFN)-γ and tumour necrosis factor ( TNF)-α. While belatacept did not affect the proliferation of CD8+ CD28− T cells, MSC reduced the percentage of CD28− T cells in the proliferating CD8+ T cell fraction by 45·9% ( P = 0·009). CD8+ CD28− T cells as effector cells in MLR in the presence of CD4+ T cell help gained CD28 expression, an effect independent of MSC. In contrast, allostimulated CD28+ T cells did not lose CD28 expression in MLR- MSC co-culture, suggesting that MSC control pre-existing CD28− T cells and not newly induced CD28− T cells. In conclusion, alloreactive CD8+ CD28− T cells that remain unaffected by belatacept treatment are inhibited by MSC. This study indicates the potential of an MSC-belatacept combination therapy to control alloreactivity. [ABSTRACT FROM AUTHOR]