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HSP90 and HSP90β Isoforms Selectively Modulate MHC Class II Antigen Presentation in B Cells¹

Josetta L. Houlihan^*,, Jennifer J. Metzler and Janice S. Blum^2,*,

^* Department of Microbiology and Immunology, Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202; Walther Oncology Center, Walther Cancer Institute, Indianapolis, IN 46202; and Department of Biology, Ball State University, Muncie, IN 47306

Two isoforms of heat shock protein (HSP) 90, and β, are abundantly expressed in the cytoplasm of cells, yet only HSP90 serves as a chaperone to potentiate epitope presentation in the context of MHC class I molecules. By contrast, the role of HSP90 isoforms in MHC class II presentation of exogenous and endogenous Ags remains less clear. Studies here using human B lymphoblasts demonstrate the importance of HSP90 and HSP90β isoforms in selectively regulating class II presentation of the diabetes autoantigen glutamic acid decarboxylase (GAD). Inactivation of HSP90 function using geldanamycin or radicicol inhibited MHC class II presentation of exogenous and endogenous GAD, but did not perturb the presentation of several other intra- and extracellular Ags. Treatment of human B cells with geldanamycin and radicicol did not alter cellular MHC class II expression, but did induce a stress response in these APCs. Yet, cell stress alone failed to perturb MHC class II presentation of GAD. HSP90 was found to associate with select Ags such as GAD in cells and ex vivo. Knockdown of HSP90 or HSP90β expression using small interfering RNA decreased the abundance of each isoform, respectively, but did not affect MHC class II expression or induce a stress response. Notably, disruption of HSP90 or HSP90β expression specifically inhibited class II presentation of the exogenous and endogenous GAD Ag. Precomplexing HSP90 with GAD Ag enhanced exogenous GAD Ag presentation. These results demonstrate a requirement for HSP90 and HSP90β in regulating class II presentation of select Ags.

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 Grant AI49589.

² Address correspondence and reprint requests to Dr. Janice S. Blum, Department of Microbiology and Immunology, Indiana Medical Science Building, Room 420, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202. E-mail address: jblum{at}iupui.edu

³ Abbreviations used in this paper: GAD, glutamic acid decarboxylase; GA, geldanamycin; RA, radicicol; HSP, heat shock protein; HSC, heat shock constitutive protein; HSA, human serum albumin; siRNA, small interfering RNA; DC, dendritic cell.