Failure of MHC class II expression in neonatal alveolar macrophages: potential role of class II transactivator.
Neonatal peritoneal and blood macrophages are known to be ineffective in antigen-presentation functions, and this manifests as inefficient MHC class II expression in response to IFN-gamma. The underlying mechanisms responsible for this maturational deficiency have not been elucidated. We show here that MHC class II expression in alveolar macrophages (AM) from neonates is also refractory to IFN-gamma stimulation. Furthermore, by examining the intracellular pathway leading to MHC class II expression, we demonstrate that the site of the impairment is at the level of transcription. Thus, expression of mRNA encoding the class II transactivator (CIITA), MHC class II (RT1.B) and invariant chain (Ii) was low or undetectable in neonatal AM stimulated with concentrations of IFN-gamma that induced adult AM to up-regulate MHC class II expression. The failure of AM from young animals to express MHC class II was not due simply to deficient IFN-gamma receptor function since IFN-gamma-responsive genes such as IRF-1, IRF-2 and IP-10 were up-regulated in a dose-dependent manner from animals of all ages investigated. Importantly, the responsiveness of neonatal AM to IFN-gamma, as determined by MHC class II expression, could be modulated to adult levels when pre-cultured in vitro. This suggests that microenvironmental factors operative in vivo may play a role in suppressing the expression of MHC class II in AM from young animals. We have investigated the role of type I interferons but did not find them to be responsible for the inability of AM from young animals to induce MHC class II in response to IFN-gamma.
Lee
P T
PT
TVW Telethon Institute for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
Holt
P G
PG
McWilliam
A S
AS
D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007150:Immunohistochemistry; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017471:Receptors, Interferon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D000096743:Interferon gamma Receptor
D000944:Antigens, Differentiation, B-Lymphocyte; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C494259:Irf1 protein, rat; C083728:MHC class II transactivator protein; C045084:invariant chain