title: IFN-gamma mediates the death of Th1 cells in a paracrine manner.
abstract: Th1 cells have different capacities to develop into memory cells based on their production of IFN-gamma. In this study, the mechanism by which a homogenous population of IFN-gamma-producing CD4 T cells was eliminated in vivo was assessed. When such cells were transferred into naive mice and activated with Ag, a striking decrease in the frequency of cells in the spleen and lung was observed. However, administration of neutralizing anti-IFN-gamma Ab at the time of Ag challenge largely prevented the elimination of such cells. To determine whether IFN-gamma was mediating its effects directly and/or indirectly, the ability of IFN-gamma to effectively signal in such cells was assessed in vitro. Indeed, there was reduced phosphorylation of STAT1 in response to IFN-gamma as well as markedly reduced expression of the IFN-gammaR beta-chain. Furthermore, transfer of such cells into IFN-gammaR-deficient mice limited their death following activation with Ag. Together, these data suggest that IFN-gamma acts in a paracrine manner to mediate the death of activated IFN-gamma-producing Th1 cells. In contrast to Ag stimulation, administration of CpG alone resulted in the elimination of Th1 cells in IFN-gammaR-/- mice. These results show that in response to Ag stimulation, the death of IFN-gamma-producing effector Th1 cells is controlled in an IFN-gamma-dependent manner, whereas in response to innate activation, the death of IFN-gamma-producing Th1 cells can occur through an IFN-gamma-independent pathway. Collectively, these data show the multiple mechanisms by which Th1 effector cells are efficiently eliminated in vivo.
authors.affiliation: Cellular Immunology Section, Human Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Foulds
authors.forename: Masashi J
authors.initials: MJ
authors.lastname: Rotte
authors.forename: Michael A
authors.initials: MA
authors.lastname: Paley
authors.forename: Babu
authors.initials: B
authors.lastname: Singh
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.forename: Chang-You
authors.initials: CY
authors.lastname: Wu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis; D002470:Cell Survival; D018899:CpG Islands / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D019899:Paracrine Communication; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D000906:Antibodies; D000941:Antigens; D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor