CD45RB ligation inhibits allergic pulmonary inflammation by inducing CTLA4 transcription.
CD45, a type I transmembrane protein tyrosine phosphatase expressed on nucleated hemopoietic cells, is prominently involved in T cell activation. Ligation of CD45RB isoforms has been associated with transplant tolerance. A recent genotyping analysis of asthma indicates a correlation with CD45 splicing. In this study, we administered an anti-CD45RB mAb (aCD45) in a murine model of allergic asthma and found that CD45RB ligation decreases allergic responses. aCD45 decreases allergen-induced pulmonary eosinophilia, bronchoalveolar lavage IL-13, IgE, and airway responses. Also, aCD45 increases the expression of CTLA4, a negative regulator of T cell activation. Furthermore, CD45RB signals no longer decrease allergic inflammation when CTLA4 is inhibited. These data support a role for CTLA4 in CD45RB-mediated inhibition of allergic inflammation. T cells and splenocytes stimulated with aCD45 exhibited increased CTLA4 levels, and analysis of CTLA4 promoter gene constructs identified a CD45RB-inducible regulatory region localized from -335 to -62 bp relative to the transcription start site. Together, these findings suggest that CD45RB signals mediate a novel role in the modulation of allergic inflammation, orchestrated by T cells through induction of CTLA4 transcription.
Jen
Kai Yu
KY
Department of Medicine, Pulmonary and Critical Medicine, School of Medicine, University of California, San Diego, CA 92093, USA.
Campo
Monica
M
He
Hongzhen
H
Makani
Samir S
SS
Velasco
German
G
Rothstein
David M
DM
Perkins
David L
DL
Finn
Patricia W
PW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002460:Cell Line; D045744:Cell Line, Tumor; D017493:Leukocyte Common Antigens / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011401:Promoter Regions, Genetic; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology*