title: IFN-gamma generates maturation-arrested dendritic cells that induce T cell hyporesponsiveness independent of Foxp3+ T-regulatory cell generation.
abstract: Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that induces the proliferation of T-helper 1 cells that contribute to allograft rejection. Surprisingly, allografts transplanted in IFN-gamma deficient mice are rapidly rejected, suggesting that this cytokine has a paradoxical role in regulating alloimmune responses. Since dendritic cells (DC) play an essential role in initiating allograft rejection the effect of IFN-gamma on DC differentiation, maturation and function in vitro were investigated. DC were differentiated with IL4/GMCSF and treated with IFN-gamma at day 0 (IFN-gamma-DC(0)) or day 5 (IFN-gamma-DC(5)) during maturation and compared with untreated DC (UT-DC). Flow cytometric analysis of IFN-gamma-DC(0) demonstrated a downregulation in the DC maturation marker CD83 by 90% whereas the expression of the inhibitory molecules ILT2, ILT3 and ILT4 were upregulated. Inhibition of relB mRNA expression (79%; p=0.01) and IL-12 (97%; p=0.02) compared to UT-DC further confirmed that IFN-gamma-DC(0) were 'maturation-arrested'. Moreover, IFN-gamma-DC(0) inhibited allogeneic T cell proliferation by 33% (p=0.02) compared to UT-DC. However, induction of T cell hyporesponsiveness by IFN-gamma-DC(0) was not regulated by the generation of CD4(+)Foxp3(+) T cells nor due to IFN-gamma induced inhibitory molecules, HLA-G and IDO. In contrast, IFN-gamma-DC(5) expressed higher levels of costimulatory molecules and MHC class II compared to UT-DC and did not cause T cell hyporesponsiveness. Thus, the timing of IFN-gamma treatment of monocytes prior to their differentiation to DC is critical for generating DC that regulate T cell function. IFN-gamma may therefore play a regulatory role in alloimmunity by acting on DC precursors.
authors.affiliation: Transplantation Immunology Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, South Australia.
authors.forename: Darling
authors.initials: D
authors.lastname: Rojas
authors.forename: Ravi
authors.initials: R
authors.lastname: Krishnan
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma