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Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA.

ABSTRACT: Diminished immune functions and chronic inflammation are hallmarks of aging. The underlying causes are not well understood. In this investigation, we show an increased reactivity of dendritic cells (DCs) from aged subjects to self-Ags as one of the potential mechanisms contributing to age-associated inflammation. Consistent with this, DCs from aged subjects display increased reactivity to intracellular human DNA, a self-Ag, by secreting enhanced quantities of type I IFN and IL-6 compared with the DCs from young subjects. Furthermore, this is accompanied by an increased up-regulation of costimulatory molecules CD80 and CD86. These DNA-primed DCs from aged subjects enhanced T cell proliferation compared with the young subjects, further substantiating our findings. Investigations of signaling mechanisms revealed that DNA-stimulated DCs from aged subjects displayed a significantly higher level of IFN regulatory factor-3 and NF-kappaB activity compared with their young counterparts. More importantly, DCs from aged subjects displayed a higher level of NF-kappaB activation at the basal level, suggesting an increased state of activation. This activated state of DCs may be responsible for their increased reactivity to self-Ags such as DNA, which in turn contributes to the age-associated chronic inflammation.

SUBMITTER: Agrawal A

PROVIDER: S-EPMC2621318 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA.

Agrawal Anshu A Tay Jia J Ton Steven S Agrawal Sudhanshu S Gupta Sudhir S

Journal of immunology (Baltimore, Md. : 1950) 20090101 2

Diminished immune functions and chronic inflammation are hallmarks of aging. The underlying causes are not well understood. In this investigation, we show an increased reactivity of dendritic cells (DCs) from aged subjects to self-Ags as one of the potential mechanisms contributing to age-associated inflammation. Consistent with this, DCs from aged subjects display increased reactivity to intracellular human DNA, a self-Ag, by secreting enhanced quantities of type I IFN and IL-6 compared with th ...[more]

PMID: 19124757

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Project description:Dendritic cells (DCs) are professional antigen-presenting cells that can recognize, capture, and process antigens. Fusing molecules targeting DCs with antigens can effectively improve the efficiency with which antigens are recognized and captured by DCs. This targeting strategy can be used for vaccine development to effectively improve the efficiency of antigen recognition and capture by DCs. The targeting sequence of porcine cytotoxic T-lymphocyte associated protein 4 (CTLA4), which binds porcine DCs, was identified in this study. Recombinant Lactobacillus reuteri (L. reuteri) expressing CTLA4-6aa (LYPPPY) and CTLA4-87aa fused to the porcine epidemic diarrhea virus (PEDV) protective antigen core neutralizing epitope (COE) were used to evaluate the ability of the two targeting motifs to bind the B7 molecule on DCs. Our results demonstrate that CTLA4-6aa could bind porcine DCs, and recombinant Lactobacillus expressing the CTLA4-6aa captured by porcine DCs was more efficient than those expressing CTLA4-87aa. In addition, the expression of DC markers, toll-like receptors, and cytokines was significantly higher in the 6aa-COE/L. reuteri-stimulated porcine DCs compared to DCs treated with 87aa-COE/L. reuteri (p<0.01) and recombinant Lactobacillus expressing CTLA4-6aa enhanced the ability of porcine DCs to activate T-cell proliferation. Our analysis of the protein structure revealed that CTLA4-87aa contains intramolecular hydrogen bonds, which may have weakened the intermolecular force between the residues on porcine CTLA4 and that on B7. In conclusion, recombinant Lactobacillus expressing CTLA4-6aa were more efficiently captured by porcine DCs and had a stronger ability to promote DC maturation and enhance T-cell proliferation. The LYPPPY motif is the optimal sequence for binding to porcine DCs. Piglets immunized with recombinant Lactobacillus showed that recombinant Lactobacillus expressing CTLA4-6aa induced significant levels of anti-PEDV-specific IgG and IgA antibody responses. Our study may promote research on DC-targeting strategies to enhance the effectiveness of porcine vaccines.

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Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA.

Publications

Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA.

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