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CD8⁺, but Not CD8^–, Dendritic Cells Tolerize Th2 Responses via Contact-Dependent and -Independent Mechanisms, and Reverse Airway Hyperresponsiveness, Th2, and Eosinophil Responses in a Mouse Model of Asthma

John R. Gordon^1,*, Fang Li, Aarti Nayyar^*, Jim Xiang and Xiaobei Zhang^*

^* Immunology Research Group, Department of Veterinary Microbiology, and The Saskatoon Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and Department of Immunology, Dalian Medical University, Dalian, Liaoning, People’s Republic of China

Splenic CD8⁺ dendritic cells reportedly tolerize T cell responses by inducing Fas ligand-mediated apoptosis, suppressing IL-2 expression, or catabolizing T cell tryptophan reserves through expression of IDO. We report in this study that CD8⁺, but not CD8^–, dendritic cells purified from the spleens of normal mice can tolerize the Th2 responses of cells from asthma phenotype mice through more than one mechanism. This tolerance could largely be reversed in vitro by anti-IL-10 or anti-TGF Ab treatment. However, loss of direct dendritic cell-T cell contact also reduced tolerance, although to a lesser extent, as did adding the IDO inhibitor 1-methyltryptophan or an excess of free tryptophan to the cultures. Within 3 wk of reconstituting asthma phenotype mice with 1 x 10⁵ OVA-pulsed CD8⁺, but not CD8^–, dendritic cells, the mice experienced a reversal of airway hyperresponsiveness, eosinophilic airway responses, and pulmonary Th2 cytokine expression. This data indicates that CD8⁺ dendritic cells can simultaneously use multiple mechanisms for tolerization of T cells and that, in vivo, they are capable of tolerizing a well-established disease complex such as allergic lung disease/asthma.