Growth factor independence-1B expression leads to defects in T cell activation, IL-7 receptor alpha expression, and T cell lineage commitment.
T cell differentiation in the thymus is dependent upon signaling through the TCR and is characterized by the resulting changes in expression patterns of CD4 and CD8 surface coreceptor molecules. Although recent studies have characterized the effects of proximal TCR signaling on T cell differentiation, the downstream integration of these signals remains largely unknown. The growth factor independence-1 (GFI1) and GFI1B transcriptional repressors may regulate cytokine signaling pathways to affect lymphocyte growth and survival. In this study, we show that Gfi1 expression is induced upon induction of the T cell program. Gfi1B expression is low and dynamic during T cell development, but is terminated in mature thymocytes. Transgenic expression of GFI1 and GFI1B in T cells allowed us to determine the functional consequences of constitutive expression. GFI1 potentiates response to TCR stimulation and IL-2, whereas GFI1B-transgenic T cells are defective in T cell activation. Moreover, GFI1B-transgenic thymocytes display reduced expression of the late-activation marker IL-7R alpha, and a decrease in CD4(-)8(+) single-positive T cells that can be mitigated by transgenic expression of BCL2 or GFI1. These data show that GFI1 and GFI1B are functionally unique, and implicate a role for GFI1 in the integration of activation and survival signals.
Doan
Loretta L
LL
Institute for Cellular Therapeutics and Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Kitay
Mary Kate
MK
Yu
Qing
Q
Singer
Alfred
A
Herblot
Sabine
S
Hoang
Trang
T
Bear
Susan E
SE
Morse
Herbert C
HC
Tsichlis
Philip N
PN
Grimes
H Leighton
HL
D000818:Animals; D001324:Autoantigens / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D003432:Cross-Linking Reagents / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology; D006182:H-Y Antigen / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000494:pharmacology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors; D019076:Transgenes / Q000276:immunology
D001324:Autoantigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C486395:Gfi1b protein, mouse; D006182:H-Y Antigen; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D020395:Receptors, Interleukin-7; D012097:Repressor Proteins; D014157:Transcription Factors; C415350:interleukin-7 receptor, alpha chain