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Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation¹

Yonglian Sun^2,*, Sarah E. Blink^*, Wenhua Liu^*, Youjin Lee^*, Bohao Chen, Julian Solway, Joel Weinstock, Lieping Chen and Yang-Xin Fu^2,*

^* Department of Pathology and Committee on Immunology, Department of Medicine, University of Chicago, Chicago, IL 60637; Department of Medicine, Tufts Medical Center, Boston, MA 02111; and Department of Dermatology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287

The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8⁺ T cells and stimulate IFN- production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN- and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.

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