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

Immunity. 1997 Aug;7(2):243-54. doi: 10.1016/s1074-7613(00)80527-0.

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 TCR alphabeta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Clonal Deletion / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Epitopes, T-Lymphocyte / genetics
  • Female
  • H-Y Antigen / genetics
  • Histocompatibility Antigens Class I / biosynthesis
  • Interferon Regulatory Factor-1
  • L Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptides / genetics
  • Peptides / immunology
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Phosphotyrosine / genetics
  • Phosphotyrosine / physiology
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Thymus Gland / cytology*
  • Thymus Gland / immunology
  • Transcription Factors / genetics
  • Transcription Factors / physiology*

Substances

  • DNA-Binding Proteins
  • Epitopes, T-Lymphocyte
  • H-Y Antigen
  • Histocompatibility Antigens Class I
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • Peptides
  • Phosphoproteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Transcription Factors
  • Phosphotyrosine