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CCL2 chemokine in central tolerance
The goal of the project is to study the role of CCL2 on dendritic cell (DC) recruitment and T cell tolerance in thymus.
CCL2 is a chemokine involved in the recruitment of immune cells during inflammation. DC can take up antigens in periphery and migrate into the thymus to mediate tolerance. Three DC subsets have been identified in mouse thymus and they all express CCR2, the main receptor for CCL2.
We separated thymocytes from stromal cells (mainly thymic epithelial cells (TEC) and DC) by percoll gradient centrifugation. We demonstrated by quantitative PCR that CCL2 was induced in stromal cells, mainly TEC (CD45-negative stromal cells), by interaction with autoreactive thymocytes. Analysis of thymic DC subsets in CCL2-deficient mice showed a decrease of the Sirp+-subset.
To study the role of CCL2 in T cell tolerance, we took advantage of mice that overexpress CCL2 in thymus. Overexpression of CCL2 in thymus of myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgenic mice (2D2 mice) induced loss of CD4 from MOG-specific T cells in thymus and lymph node (LN). LN T cells from mice overexpressing CCL2 in thymus responded poorly to MOG and these mice were resistant to experimental autoimmune encephalomyelitis.
We conclude that CCL2 induced by interaction between autoreactive thymocytes and stromal cells is involved in regulation of T cell tolerance and we propose that DC recruitment plays a role.