CD28 and CTLA4 coordinately regulate airway inflammatory cell recruitment and T-helper cell differentiation after inhaled allergen.
Airway inflammation after inhaled allergen exposure requires the recruitment, activation, and differentiation of antigen-specific T cells into T helper (Th) 2 effector cells. These processes are regulated not only by antigen engagement of the T-cell receptor, but also by specific accessory molecules on the surface of the T cell. We examined how the balance of signals derived through the CD28 and cytotoxic T-lymphocyte antigen (CTLA) 4 receptors modulate the outcome of inhaled antigen exposure in a murine model of allergic airway inflammation. Mice deficient in CD28 have defective Th2 cell development and failed to develop inflammation after sensitization and inhaled challenge with ovalbumin. Prevention of B7-CTLA4 interactions in CD28-deficient mice restored lymphocyte but not eosinophil recruitment to the airway. Analysis of cytokine gene expression revealed that T cells from CD28-deficient mice failed to differentiate into Th2 cells in either the presence or absence of B7-dependent signals, and therefore did not recruit eosinophils to the airway. Thus, the processes of T-cell recruitment to the airway and T-cell differentiation have distinct requirements for signals mediated through the CD28 and CTLA4 receptors, demonstrating that these receptors are important regulatory components in the development of allergic airway inflammation.
Burr
J S
JS
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kimzey
S L
SL
Randolph
D R
DR
Green
J M
JM
D000069594:Abatacept; D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D018796:Immunoconjugates; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011014:Pneumonia / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000485:Allergens; D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000069594:Abatacept; D010047:Ovalbumin