Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis.
Antigen-presenting cells (APC) are considered to play a critical role in promoting the (re)activation of potentially autoreactive T cells in multiple sclerosis (MS), an inflammatory demyelinating disorder of the central nervous system (CNS). B7-H1 (PD-L1) is a novel member of the B7 family proteins which exert costimulatory and immune regulatory functions. Here we characterize the expression and functional activity of B7-H1 expressed on monocytes and dendritic cells (DC) of healthy donors and MS patients. B7-H1 is constitutively expressed on monocytes and differentially matured DC, but not on B cells. IFN-beta, the principle immune modulatory agent used for the treatment of MS, strongly enhances B7-H1 expression on monocytes and semi-matured DC, but not B cells, in vitro. Importantly, B7-H1 expressed on APC strongly inhibits autologous CD4 T-cell activation. Neutralization of B7-H1 on monocytes or differentially matured monocyte-derived DC markedly increases the secretion of the pro-inflammatory cytokines, IFN-gamma and IL-2, T-cell proliferation, and the expression of T-cell activation markers. B7-H1 exhibits strong inhibitory effects when expressed on monocytes, immature or semi-mature DC, but less so when expressed on fully matured DC. B7-H1-dependent immune inhibition is in part mediated by CD4/CD25+ regulatory T cells. There is no difference in the baseline expression levels of monocytic B7-H1 between untreated MS patients and healthy donors. However, both groups show a significant concentration-dependent up-regulation of B7-H1 mRNA and protein in response to IFN-beta in vitro. Serial measurements of B7-H1 mRNA in MS patients before and 6 months after initiation of IFN-beta therapy corroborated the relevance of these results in vivo: Nine of nine patients showed a significant increase in B7-H1 mRNA levels after 6 months of IFN-beta therapy (median 1.04 vs. 8.78; p<0.05, two-sided t-test). Accordingly, protein expression of B7-H1 on monocytes was up-regulated after 24 h of IFN-beta application. In summary, B7-H1 expressed on APC acts as a strong inhibitor of autologous CD4 T-cell activation and may thus contribute to the maintenance of peripheral immune tolerance. IFN-beta up-regulates B7-H1 in vitro and in MS patients in vivo and might represent a novel mechanism how IFN-beta acts as a negative modulator on APC T-cell interactions in the periphery.
Schreiner
Bettina
B
Department of General Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany.
Mitsdoerffer
Meike
M
Kieseier
Bernd C
BC
Chen
Lieping
L
Hartung
Hans-Peter
HP
Weller
Michael
M
Wiendl
Heinz
H
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D015703:Antigens, CD; D018122:B7-1 Antigen / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000187:drug effects / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D010455:Peptides; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D016899:Interferon-beta; D007371:Interferon-gamma