[PDF][PDF] The interferon regulatory transcription factor IRF-1 controls positive and negative selection of CD8+ thymocytes

JM Penninger, C Sirard, HW Mittrücker, A Chidgey… - Immunity, 1997 - cell.com
JM Penninger, C Sirard, HW Mittrücker, A Chidgey, I Kozieradzki, M Nghiem, A Hakem…
Immunity, 1997cell.com
Little is known about the molecular mechanisms and transcriptional regulation that govern T
cell selection processes and the differentiation of CD4+ and CD8+ T cells. Mice lacking the
interferon regulatory transcription factor-1 (IRF-1) have reduced numbers of mature CD8+
cells within the thymus and peripheral lymphatic organs. Here we show that positive and
negative T cell selection of two MHC class I–restricted TCRαβ transgenes, HY and P14, are
impaired in IRF-1−/− mice. The absence of IRF-1 resulted in decreased expression of LMP2 …
Abstract
Little is known about the molecular mechanisms and transcriptional regulation that govern T cell selection processes and the differentiation of CD4+ and CD8+ T cells. Mice lacking the interferon regulatory transcription factor-1 (IRF-1) have reduced numbers of mature CD8+ cells within the thymus and peripheral lymphatic organs. Here we show that positive and negative T cell selection of two MHC class I–restricted TCRαβ transgenes, H-Y and P14, are impaired in IRF-1−/− mice. The absence of IRF-1 resulted in decreased expression of LMP2, TAP1, and MHC class I on thymic stromal cells. Despite decreased MHC class I expression on IRF-1−/− thymic stromal cells, the defect in CD8+ T cells development did not reside in the thymic environment, and IRF-1−/− stromal cells can fully support development of CD8+ thymocytes in in vivo bone marrow chimeras and in vitro reaggregation cultures. Moreover, IRF-1−/− thymocytes displayed impaired TCR-mediated signal transduction, and the induction of negative selection in TCR Tg thymocytes from IRF-1−/− mice required a 1000-fold increase in selecting peptide. We also provide evidence that IRF-1 is mainly expressed in mature, but not immature, thymocytes and that expression of IRF-1 in immature thymocytes is induced after peptide-specific TCR activation. These results indicate that IRF-1 regulates gene expression in developing thymocytes required for lineage commitment and selection of CD8+ thymocytes.
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