Enhanced tolerance to autoimmune uveitis in CD200-deficient mice correlates with a pronounced Th2 switch in response to antigen challenge.
A single exposure to inhaled Ag 10 days before immunization leads to long term, Ag-specific tolerance. Respiratory tract myeloid APCs are implicated, but how regulation is invoked, and how tolerance is sustained are unclear. This study examines the in vivo function of the myeloid regulatory molecule CD200 in the process of tolerance induction. Despite earlier onset of experimental autoimmune uveitis in sham-tolerized, CD200-deficient mice, disease incidence and subsequent severity were actually reduced compared with those in wild-type mice. Protection was more effective and long term, lasting at least 28 days. Halting disease progression and tolerance in CD200(-/-) mice correlated with a marked increase in Th2-associated cytokine production by Ag-challenged splenocytes. Reduced overall disease and enhanced tolerance in the CD200-deficient mice in this model system were unexpected and may be related to altered populations of MHC class II(low) APC in the respiratory tract compared with wild-type mice together with associated activation of STAT6 in draining lymph nodes of tolerized mice. These data indicate that in the absence of default inhibitory CD200 receptor signaling, alternative, powerful regulatory mechanisms are invoked. This may represent either permissive dominant Th2 activation or an altered hierarchy of negative signaling by other myeloid cell-expressed regulatory molecules.
Taylor
Neil
N
College of Medicine and Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
McConachie
Karen
K
McConnachie
Karen
K
Calder
Claudia
C
Dawson
Rosemary
R
Dick
Andrew
A
Sedgwick
Jonathon D
JD
Liversidge
Janet
J
D000280:Administration, Inhalation; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000940:Antigenic Variation / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005136:Eye Proteins / Q000008:administration & dosage / Q000276:immunology; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D016130:Immunophenotyping; D047468:Immunoprecipitation; D008168:Lung / Q000166:cytology / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D012177:Retinol-Binding Proteins / Q000008:administration & dosage / Q000276:immunology; D050800:STAT6 Transcription Factor; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology; D014605:Uveitis / Q000276:immunology*; D000099214:Retinol-Binding Proteins, Interstitial
D016207:Cytokines; D005136:Eye Proteins; D008562:Membrane Glycoproteins; D012177:Retinol-Binding Proteins; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D000099214:Retinol-Binding Proteins, Interstitial; C492346:CD200 receptor, mouse; C494100:Stat6 protein, mouse