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

Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0815, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(1):256-64. DOI: 10.4049/jimmunol.181.1.256
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Gary Hardiman, Sep 27, 2015
19 Reads
  • Source
    • "Another link between cell stress responses and immune regulation is the relationship between the UPR and UPR-dependent inflammatory cytokines that promote tumor growth (Mumm and Oft 2008; Wheeler et al. 2008; Zhang and Kaufman 2008). Endoplasmic reticulum stress can be ''transmitted'' from tumor cells to macrophages that have been treated with conditioned medium of murine cancer cells experiencing endoplasmic reticulum stress in vitro. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span.
    Genes & Development 07/2014; 28(14):1533-1543. DOI:10.1101/gad.241125.114 · 10.80 Impact Factor
  • Source
    • "To verify whether TFM-C is capable of inducing ER stress in microglia, the mouse microglial BV2 cell line was used. Specifically, we measured mRNA of HERP and IL-23p19, both of which are induced by ER stress [5,6,35]. BV2 cells were pre-treated with TFM-C (30 and 50 µM) for 2 hours and then stimulated with LPS for 3, 6, 12 and 24 hours in the presence or absence of TFM-C, which showed significant dose-dependent up-regulation of IL-23p19 and HERP (Figure 3B). Figure 3C shows that co-treatment of LPS with TFM-C led to increased accumulation of HERP in microglial cells (Figure 3C, panel a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1β, IL-12 and IL-17, enhanced that of TNF-α and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-α release in microglial cells through a process involving intracellular retention, but induced TNF-α secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL-17 and IFN-γ by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro-inflammatory conditions.
    PLoS ONE 12/2013; 8(12):e83119. DOI:10.1371/journal.pone.0083119 · 3.23 Impact Factor
  • Source
    • "Virtually no effect was seen on mRNA production of TNF-α and IL-8, while TFM-C increased IL-6 mRNA between 6 and 12 h. To verify whether TFM-C induced an ER stress response in U937 cells, we measured mRNA of HERP and IL-23p19, both of which have been associated with induction of ER stress [24,26,27]. This showed significant up-regulation of both genes by TFM-C while the housekeeping gene GAPDH was not affected (Figure 1D). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Celecoxib, a highly specific cyclooxygenase-2 (COX-2) inhibitor has been reported to have COX-2-independent immunomodulatory effects. However, celecoxib itself has only mild suppressive effects on arthritis. Recently, we reported that a 4-trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2-inhibitory activity inhibits secretion of IL-12 family cytokines through a COX-2-independent mechanism that involves Ca2+-mediated intracellular retention of the IL-12 polypeptide chains. In this study, we explored the capacity of TFM-C as a new therapeutic agent for arthritis. To induce collagen-induced arthritis (CIA), DBA1/J mice were immunized with bovine type II collagen (CII) in Freund's adjuvant. Collagen antibody-induced arthritis (CAIA) was induced in C57BL/6 mice by injecting anti-CII antibodies. Mice received 10 μg/g of TFM-C or celecoxib every other day. The effects of TFM-C on clinical and histopathological severities were assessed. The serum levels of CII-specific antibodies were measured by ELISA. The effects of TFM-C on mast cell activation, cytokine producing capacity by macrophages, and neutrophil recruitment were also evaluated. TFM-C inhibited the severity of CIA and CAIA more strongly than celecoxib. TFM-C treatments had little effect on CII-specific antibody levels in serum. TFM-C suppressed the activation of mast cells in arthritic joints. TFM-C also suppressed the production of inflammatory cytokines by macrophages and leukocyte influx in thioglycollate-induced peritonitis. These results indicate that TFM-C may serve as an effective new disease-modifying drug for treatment of arthritis, such as rheumatoid arthritis.
    Arthritis research & therapy 01/2012; 14(1):R9. DOI:10.1186/ar3683 · 3.75 Impact Factor
Show more