Lentivirus-activated T regulatory cells suppress T helper cell interleukin-2 production by inhibiting nuclear factor of activated T cells 2 binding to the interleukin-2 promoter.
Using the feline immunodeficiency virus (FIV) model for AIDS lentivirus infection, we previously demonstrated that Treg cells from FIV-infected cats up-regulate membrane-associated tumor growth factor beta (mTGF-ß) during the course of infection and that activated T lymphocytes up-regulate TGF-ß receptor II (TGF-ßRII) during the course of infection. Furthermore, we have demonstrated that autologous coculture of Tregs with Th cells from FIV-infected cats leads to suppression of interleukin (IL)-2 production and loss of proliferation in a TGF-ß-dependent fashion. Nuclear factor of activated T cells (NFAT) 2 has been identified as integral to effector Th cell maturation and function by promoting IL-2 transcription. Therefore, we questioned whether NFAT2 expression might be altered by TGF-β signaling. Feline NFAT2 exon sequences were identified based upon sequence homology to human and murine NFAT2. Following stimulation, IL-2 and NFAT2 mRNA levels were similarly increased in both FIV(-) and FIV(+) cats. Activated CD4(+)CD25(-) cells from both FIV(-) and FIV(+) cats cocultured with autologous CD4(+)CD25(+) cells or treated with TGF-β demonstrated decreased IL-2 production; however, NFAT2 mRNA levels were unaffected. Although NFAT2 mRNA levels were unaffected, chromatin immunoprecipitation (ChIP) for NFAT2 indicated decreased NFAT2 binding at the IL-2 promoter in suppressed Th cells. These data suggest that TGF-β-mediated Treg cell suppression of IL-2 transcription is modulated through alterations in NFAT2 binding to the IL-2 promoter.
Immunology Program, Department of Population Health and Pathobiology, North Carolina State University College of Veterinary Medicine , Raleigh, North Carolina.
Liping
L
Meng
Mary
M
Tompkins
Michelle
M
Miller
Jonathan
J
Fogle
D000595:Amino Acid Sequence; D000818:Animals; D002415:Cats; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016089:Immunodeficiency Virus, Feline / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D016180:Lentivirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology; D008198:Lymph Nodes / Q000166:cytology / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D016415:Sequence Alignment; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000821:virology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology; D015854:Up-Regulation
D007376:Interleukin-2; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta