CD4+ T cells from simian immunodeficiency virus disease-resistant sooty mangabeys produce more IL-2 than cells from disease-susceptible species: involvement of p300 and CREB at the proximal IL-2 promoter in IL-2 up-regulation.
IL-2 is an important cytokine required for the physiological function of CD4(+) T cells. Immunological unresponsiveness-anergy- of CD4(+) T cells is characterized by the inability of these cells to synthesize IL-2. Both progressive HIV infection leading to AIDS in humans and SIV infection in rhesus macaques (RM) are associated with dysregulation of IL-2 synthesis. In certain nonhuman primate species, such as sooty mangabeys (SM), SIV infection does not lead to AIDS. We have shown that this is associated with the resistance of the CD4(+) T cells from SM to undergo anergy in vitro. In this study, we show that CD4(+) T cells from SM spontaneously synthesize 2- to 3-fold higher levels of IL-2 than corresponding cells from RM. Proximal IL-2 promoter constructs derived from SM show significantly higher activity than the RM-derived constructs in primary CD4(+) T cells, which is associated with an element at approximately nt -200. Activity of both constructs was up-regulated by p300 and down-regulated by CREB to a similar degree. Chromatin immunoprecipitation analysis showed significantly higher binding of p300 and lower binding of CREB to the SM promoter in vivo. Two single nucleotide substitutions present in the SM sequence around position -200 and -180 seem to increase the affinity of these sites for the binding of transcription factors, one of which was identified as Oct-1. These unique characteristics of the proximal IL-2 promoter in SM therefore can represent one of the mechanisms contributing to the resistance of these cells to undergo anergy.
Bostik
Pavel
P
Department of Pathology and Laboratory Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA. Pavel.Bostik@emory.edu
Noble
Erika S
ES
Stephenson
Susan T
ST
Villinger
Francois
F
Ansari
Aftab A
AA
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D050882:CREB-Binding Protein / Q000378:metabolism; D016665:Cercocebus atys / Q000235:genetics / Q000276:immunology*; D017635:Clonal Anergy / Q000235:genetics; D004198:Disease Susceptibility; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008253:Macaca mulatta / Q000235:genetics / Q000276:immunology; D008992:Monkey Diseases / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation
D006657:Histones; D007376:Interleukin-2; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein