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CD80 Costimulation Is Required for Th2 Cell Cytokine Production But Not for Antigen-Specific Accumulation and Migration into the Lung¹

Nicola L. Harris^*, Melanie Prout^*, Robert J. Peach, Barbara Fazekas de St. Groth and Franca Ronchese^2,*

^* Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543; and Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Sydney, New South Wales, Australia

The CD28 ligands CD80 and CD86 are expressed on APC, and both provide costimulatory function. However, the reason for the expression of two separate CD28 ligands remains unclear. We have previously shown that blockade of CD80 costimulation by Y100F-Ig, a CTL-associated Ag-4 (CTLA4)-Ig mutant that does not bind CD86, inhibits the development of lung inflammatory immune responses, but does not affect blood eosinophilia or Ab production. Each of those responses was inhibited by treatment with CTLA4-Ig, which binds both CD80 and CD86. To clarify the mechanism underlying these observations we have developed a model of lung inflammation using adoptively transferred CD4⁺ T cells expressing a V11⁺V3⁺ transgenic TCR specific for I-E^k and moth cytochrome c. Treatment with Y100F-Ig inhibited the induction of lung eosinophilia in adoptively transferred mice. However, Y100F-Ig did not detectably affect the accumulation of Ag-specific T cells at the site of peptide deposit or in the draining lymphoid tissues. Acquisition of an activated phenotype and expression of adhesion molecules required for migration into the lung were modestly affected. Importantly, treatment with Y100F-Ig diminished the ability of T cells to produce the cytokines IL-4 and IL-5 following intranasal challenge with Ag. All the responses examined were severely inhibited by treatment with CTLA4-Ig. We conclude that T cells require CD80 costimulation for the optimal production of IL-5 following intranasal administration of Ag. Decreased IL-5 production is the most likely explanation for the diminished airway eosinophilia observed.

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