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 antige n (CTL)A-4 antagonist CTLA4 immunoglobulin (Ig) inhibits eosinophilic airwa y inflammation in Schistosoma mansoni-sensitized and airvay-challenged mice . In the present study, the importance of CD28 as well as the individual ro les 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 I,IgE or eosinophilic airway inflammation after antigen challenge. However, a lymphocytic infiltrate and continued production of interferon-g amma was observed in these animals. Thus, CD28 is not essential for the ini tial recruitment of lymphocytes into antigen-challenged airways but critica lly regulates the allergic T-helper 2 phenotype. We next determined by poly merase chain reaction and flow cytometry that CD80 and CD86 molecules an co nstitutively expressed in the naive murine lung and on eosinophils in the a llergic lung, suggesting a potential important role for both ligands in the development of asthma. Combined anti-CD80/anti-CD86 treatment throughout t he antigen challenge period fully blocked the development of allergic airwa ys, whereas a partial reduction was observed in mice treated with either an ti-CD80 or anti-CD86 antibody alone. However, only anti-CD86 blocked system ic IgE production. Therefore, signaling through either CD80 or CD86 is suff icient to generate a partial local allergic response, whereas CD86 costimul ation is essential to induce systemic allergic (IgE) reactions. Finally, co mbined anti-B7 monoclonal antibody treatment after sensitization reduced ai rway 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 express ion on different cells and in different organs on subsequent CD28/B7-mediat ed immune events, including the potential for CD28/B7 blockade in the treat ment of atopic airway disease in people.