Formation of IL-7Ralphahigh and IL-7Ralphalow CD8 T cells during infection is regulated by the opposing functions of GABPalpha and Gfi-1.
IL-7 is essential for the survival of naive and memory T cells, and IL-7 receptor alpha-chain (IL-7Ralpha) expression is dynamically regulated in activated CD8 T cells during acute viral and bacterial infections. Most virus-specific CD8 T cells become IL-7Ralpha(low) and are relatively short-lived, but some escape IL-7Ralpha repression (referred to as IL-7Ralpha(high) memory precursor effector cells) and preferentially enter the memory CD8 T cell pool. How antiviral effector CD8 T cells regulate IL-7Ralpha expression in an "on and off" fashion remains to be characterized. During lymphocytic choriomeningitis virus infection, we found that opposing actions of the transcription factors GABPalpha (GA binding protein alpha) and Gfi-1 (growth factor independence 1) control IL-7Ralpha expression in effector CD8 T cells. Specifically, GABPalpha was required for IL-7Ralpha expression in memory precursor effector cells, and this correlated with hyperacetylation of the Il7ra promoter. In contrast, Gfi-1 was required for stable IL-7Ralpha repression in effector CD8 T cells and acted by antagonizing GABPalpha binding and recruiting histone deacetylase 1, which deacetylated the Il7ra promoter. Thus, Il7ra promoter acetylation and activity was dependent on the reciprocal binding of GABPalpha and Gfi-1, and these data provide a biochemical mechanism for the generation of stable IL-7Ralpha(high) and IL-7Ralpha(low) states in virus-specific effector CD8 T cells.
Chandele
Anmol
A
Department of Immunobiology, Yale Medical School, New Haven, CT 06511, USA.
Joshi
Nikhil S
NS
Zhu
Jinfang
J
Paul
William E
WE
Leonard
Warren J
WJ
Kaech
Susan M
SM
D000107:Acetylation; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007156:Immunologic Memory; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D012190:Retroviridae / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; C495656:Gabpa protein, mouse; C079873:Gfi1 protein, mouse; D006657:Histones; D020395:Receptors, Interleukin-7; D014157:Transcription Factors