CD28 interactions with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice.
Previous studies have shown that the pan CD28/cytotoxic T lymphocyte antigen (CTL)A-4 antagonist CTLA4 immunoglobulin (Ig) inhibits eosinophilic airway inflammation in Schistosoma mansoni-sensitized and airway-challenged mice. In the present study, the importance of CD28 as well as the individual roles of CD80 and CD86 were examined in this system using wild-type and CD28 knockout (KO) mice. Unlike wild-type controls, CD28KO mice did not produce systemic IgE or eosinophilic airway inflammation after antigen challenge. However, a lymphocytic infiltrate and continued production of interferon-gamma was observed in these animals. Thus, CD28 is not essential for the initial recruitment of lymphocytes into antigen-challenged airways but critically regulates the allergic T-helper 2 phenotype. We next determined by polymerase chain reaction and flow cytometry that CD80 and CD86 molecules are constitutively expressed in the naive murine lung and on eosinophils in the allergic lung, suggesting a potential important role for both ligands in the development of asthma. Combined anti-CD80/anti-CD86 treatment throughout the antigen challenge period fully blocked the development of allergic airways, whereas a partial reduction was observed in mice treated with either anti-CD80 or anti-CD86 antibody alone. However, only anti-CD86 blocked systemic IgE production. Therefore, signaling through either CD80 or CD86 is sufficient to generate a partial local allergic response, whereas CD86 costimulation is essential to induce systemic allergic (IgE) reactions. Finally, combined anti-B7 monoclonal antibody treatment after sensitization reduced airway eosinophilia and interleukin (IL)-4/IL-5 cytokine secretion consistent with an ongoing role for CD28/B7 interactions in the effector phase of the disease. These results emphasize the importance of differential B7 expression on different cells and in different organs on subsequent CD28/B7-mediated immune events, including the potential for CD28/B7 blockade in the treatment of atopic airway disease in people.
Mathur
M
M
Department of Pediatrics, The Ben May Institute for Cancer Research, Chicago, Illinois, USA.
Herrmann
K
K
Qin
Y
Y
Gulmen
F
F
Li
X
X
Krimins
R
R
Weinstock
J
J
Elliott
D
D
Bluestone
J A
JA
Padrid
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000947:Antigens, Helminth / Q000008:administration & dosage; D001249:Asthma / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051940:B7-2 Antigen; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000209:etiology; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012550:Schistosoma mansoni / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000947:Antigens, Helminth; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497965:Cd86 protein, mouse; D017931:DNA Primers; D008562:Membrane Glycoproteins; D007073:Immunoglobulin E