KDEL-retained antigen in B lymphocytes induces a proinflammatory response: a possible role for endoplasmic reticulum stress in adaptive T cell immunity.
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-gamma and TNF-alpha, 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.
Wheeler
Matthew C
MC
Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0815, USA.
Rizzi
Marta
M
Sasik
Roman
R
Almanza
Gonzalo
G
Hardiman
Gary
G
Zanetti
Maurizio
M
D020816:Amino Acid Motifs; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000276:immunology*; D020869:Gene Expression Profiling; D016678:Genome / Q000235:genetics; D007109:Immunity / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics; D019076:Transgenes; D015854:Up-Regulation
D000941:Antigens; D053760:Interleukin-23 Subunit p19