The interferon regulatory transcription factor IRF-1 controls positive and negative selection of CD8+ thymocytes.
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.
Penninger
J M
JM
Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada. Jpenning@amgen.com
Sirard
C
C
Mittrücker
H W
HW
Chidgey
A
A
Kozieradzki
I
I
Nghiem
M
M
Hakem
A
A
Kimura
T
T
Timms
E
E
Boyd
R
R
Taniguchi
T
T
Matsuyama
T
T
Mak
T W
TW
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D005260:Female; D006182:H-Y Antigen / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D050856:Interferon Regulatory Factor-1; D007739:L Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D019000:Phosphotyrosine / Q000235:genetics / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D006182:H-Y Antigen; D015395:Histocompatibility Antigens Class I; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010455:Peptides; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014157:Transcription Factors; D019000:Phosphotyrosine