THE INTERFERON REGULATORY TRANSCRIPTION FACTOR IRF-1 CONTROLS POSITIVE AND NEGATIVE SELECTION OF CD8(+) THYMOCYTES

Little is known about the molecular mechanisms and transcriptional reg ulation 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(+) c ells within the thymus and peripheral lymphatic organs. Here we show t hat positive and negative T cell selection of two MHC class I-restrict ed TCR alpha beta transgenes, H-Y and P14, are impaired in IRF-1(-/-) mice. The absence of IRF-1 resulted in decreased expression of LMP2, T AP1, and MHC class I on thymic stromal cells. Despite decreased MHC cl ass 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(+) thymo cytes in in vivo bone marrow chimeras and in vitro reaggregation cultu res. Moreover, IRF-1(-/-) thymocytes displayed impaired TCR-mediated s ignal transduction, and the induction of negative selection in TCR Tg thymocytes from IRF-1(-/-) mice required a 1000-fold increase in selec ting peptide. We also provide evidence that IRF-1 is mainly expressed in mature, but not immature, thymocytes and that expression of IRF-1 i n immature thymocytes is induced after peptide-specific TCR activation . These results indicate that IRF-1 regulates gene expression in devel oping thymocytes required for lineage commitment and selection of CD8( +) thymocytes.