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KDEL-Retained Antigen in B Lymphocytes Induces a Proinflammatory Response: A Possible Role for Endoplasmic Reticulum Stress in Adaptive T Cell Immunity^1,2

Matthew C. Wheeler^*,, Marta Rizzi^*, Roman Sasik^*,, Gonzalo Almanza^*, Gary Hardiman^*, and Maurizio Zanetti^3,*,

^* Laboratory of Immunology, Department of Medicine and Moores Cancer Center, Biomedical Sciences Program, and Biomedical Genomics Microarray, La Jolla, CA 92093

Generally, APCs activate CD4 T cells against peptides derived from exogenous Ag in the context of MHC II molecules. In this study, using transgenic B lymphocytes as model APCs, we demonstrate CD4 T cell priming in vivo against peptides derived from endogenously synthesized Ag targeted either to the cytosol or to the endoplasmic reticulum (ER). Surprisingly, priming by Ag containing the KDEL-retention motif yielded higher levels of two important proinflammatory cytokines, IFN- and TNF-, in responding CD4 T cells. Importantly, we found that KDEL-mediated retention of Ag up-regulates ER-stress responsive genes in primary B lymphocytes. We also found that thapsigargin treatment of A20 lymphoma cells up-regulates transcription of ER stress and proinflammatory genes along with IL-23p19. Induction of ER stress by thapsigargin also up-regulated IL-23p19 in primary B lymphocytes, macrophages, and bone marrow-derived dendritic cells. We conclude that perturbation of the secretory pathway and/or ER stress play an important role in modulating the gene program in professional APCs and in shaping CD4 T cell responses in vivo. These findings are relevant to a better understanding of the immune response after infection by viral and bacterial pathogens and the pathogenesis of certain autoimmune diseases.

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 R01CA 92119, University of California, La Jolla, CA 92093.

² The sequences presented in this article have been submitted to EBI Array Express Database (accession number pending).

³ Address correspondence and reprint requests to Dr. Maurizio Zanetti, Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0815. E-mail address: mzanetti{at}ucsd.edu

⁴ Abbreviations used in this paper: ER, endoplasmic reticulum; UPR, unfolded protein response; p, plasmid; qRT-PCR, quantitative RT-PCR.