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CD45RB Ligation Inhibits Allergic Pulmonary Inflammation by Inducing CTLA4 Transcription¹

Kai Yu Jen^2,*, Monica Campo^2,*, Hongzhen He^*, Samir S. Makani^*, German Velasco^*, David M. Rothstein, David L. Perkins^* and Patricia W. Finn^3,*

^* Department of Medicine, Pulmonary and Critical Medicine, School of Medicine, University of California, San Diego, CA 92093; and Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510

CD45, a type I transmembrane protein tyrosine phosphatase expressed on nucleated hemopoietic cells, is prominently involved in T cell activation. Ligation of CD45RB isoforms has been associated with transplant tolerance. A recent genotyping analysis of asthma indicates a correlation with CD45 splicing. In this study, we administered an anti-CD45RB mAb (aCD45) in a murine model of allergic asthma and found that CD45RB ligation decreases allergic responses. aCD45 decreases allergen-induced pulmonary eosinophilia, bronchoalveolar lavage IL-13, IgE, and airway responses. Also, aCD45 increases the expression of CTLA4, a negative regulator of T cell activation. Furthermore, CD45RB signals no longer decrease allergic inflammation when CTLA4 is inhibited. These data support a role for CTLA4 in CD45RB-mediated inhibition of allergic inflammation. T cells and splenocytes stimulated with aCD45 exhibited increased CTLA4 levels, and analysis of CTLA4 promoter gene constructs identified a CD45RB-inducible regulatory region localized from –335 to –62 bp relative to the transcription start site. Together, these findings suggest that CD45RB signals mediate a novel role in the modulation of allergic inflammation, orchestrated by T cells through induction of CTLA4 transcription.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI053878 (to P.W.F.), HL081663 (to P.W.F.), and AI064343 (to D.M.R.).

² K.Y.J. and M.C. contributed equally to the work presented in this article.

³ Address correspondence and reprint requests to Dr. Patricia W. Finn, Department of Medicine, Pulmonary and Critical Care Division, School of Medicine, University of California, San Diego, 9500 Gilman Drive 0643, San Diego, CA 92093. E-mail address: pwfinn{at}ucsd.edu

⁴ Abbreviations used in this paper: Treg, regulatory T cell; aCD45, anti-CD45RB mAb; BAL, bronchoalveolar lavage; aCTLA4, anti-CTLA4 mAb.