The defect in CD4+CD25− cell conversion into CD4+CD25+ regulatory cells in NOD mice can be rescued by treatment with "normal" antigen presenting cells (128.3)

Abstract

Abstract NOD mice are unable to convert CD4+CD25− cells into functional CD4+CD25+ regulatory cells in vivo. To analyze this defect, we reciprocally transferred CD4+CD25− cells into NOD and B6.g7 (B6 mice expressing NOD I-Ag7) mice. In NOD recipients, transferred B6.g7 CD4+CD25− cells were unable to convert, while in B6.g7 mice, transferred NOD CD4+CD25− cells converted as effectively as controls, suggesting that it may be the NOD APC that are defective in the conversion process. To test this, we co-transferred B6.g7 DC (APC) along with NOD CD4+CD25− T cells into NOD mice. Providing NOD mice with non-defective APC rescued their ability to convert. Interestingly, although Foxp3 expression did not, granzyme B expression did correlate with regulatory ability in converted CD4+CD25+ cells: NOD CD4+CD25− cells that upregulated CD25 after transfer into NOD mice expressed comparable Foxp3, but lower levels of granzyme B and were unable to regulate, whereas converted CD4+CD25+ cells from B6 controls or NOD mice treated with B6.g7 DC expressed high levels of granzyme B and were able to regulate. Taken together, these data suggest that the failure of NOD CD4+CD25− cells to convert into functional CD4+CD25+ regulatory cells in NOD mice may be due to a defect in the ability of NOD APC to induce granyme B expression in the converted cells. Supported by NIH grant AI064421 and the KY Challenge for Excellence Fund.