Blockade of CD28/B7 co-stimulation by mCTLA4-Hgamma1 inhibits antigen-induced lung eosinophilia but not Th2 cell development or recruitment in the lung.
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-Hgamma1) which binds to B7 molecules on antigen-presenting cells, thereby preventing their interaction with T cell-expressed CD28. mCTLA4-Hgamma1-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-Hgamma1-transgenic and normal mice. Also, lung lymphocytes from immunized mCTLA4-Hgamma1-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-Hgamma1. We conclude that mCTLA4-Hgamma1 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.
Harris
N
N
Malaghan Institute of Medical Research, Wellington School of Medicine, New Zealand.
Campbell
C
C
Le Gros
G
G
Ronchese
F
F
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018106:CD28 Antigens / Q000502:physiology*; D060908:CTLA-4 Antigen; D005260:Female; D018796:Immunoconjugates; D015848:Interleukin-5 / Q000502:physiology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D015848:Interleukin-5; D000069594:Abatacept; D010047:Ovalbumin