Blockade of CD28/B7 co‐stimulation by mCTLA4‐Hγ1 inhibits antigen‐induced lung eosinophilia but not Th2 cell development or recruitment in the lung

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Abstract
We have studied the role of the CD28/B7 co‐stimulatory pathway in the development of a Th2‐type lung immune response. Mice injected two or three times intraperitoneally with ovalbumin in alum adjuvant and then re‐exposed to the same antigen by intranasal (i.n.) inoculation show infiltration of the lung tissue and appearance in the broncho‐alveolar lavage (BAL) fluid of significant numbers of eosinophils and lymphocytes, in a pattern which is reminiscent of asthmatic inflammation. The accumulation of eosinophils in the airways is completely dependent on interleukin (IL)‐5 secretion by CD4+ T cells. We have used mice transgenic for a soluble form of murine CTLA‐4 (mCTLA4‐Hγ1) which binds to B7 molecules on antigen‐presenting cells, thereby preventing their interaction with T cell‐expressed CD28. mCTLA4‐Hγ1‐transgenic mice immunized intraperitoneally and challenged i.n. with ovalbumin failed to generate any eosinophil infiltration, suggesting that little or no IL‐5 was secreted in the lungs of these mice. In contrast with the complete lack of eosinophils, the numbers and phenotypes of infiltrating lymphocytes were comparable in the lungs of mCTLA4‐Hγ1‐transgenic and normal mice. Also, lung lymphocytes from immunized mCTLA4‐Hγ1‐transgenic and normal mice could be shown to secrete comparable amounts of IL‐4 and IL‐5 when stimulated in culture in the absence of mCTLA4‐Hγ1. We conclude that mCTLA4‐Hγ1 can efficiently block the production of IL‐5 during in vivo responses and inhibit eosinophil recruitment, but that it does not block the development of CD4+ T cells into Th2 cells with the potential to secrete IL‐5.