McKee, A.S. et al. Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proc. Natl. Acad. Sci. USA 110, E1122-E1131

Clinical Immunology Division, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2013; 110(12). DOI: 10.1073/pnas.1300392110
Source: PubMed


Many vaccines include aluminum salts (alum) as adjuvants despite little knowledge of alum's functions. Host DNA rapidly coats injected alum. Here, we further investigated the mechanism of alum and DNA's adjuvant function. Our data show that DNase coinjection reduces CD4 T-cell priming by i.m. injected antigen + alum. This effect is partially replicated in mice lacking stimulator of IFN genes, a mediator of cellular responses to cytoplasmic DNA. Others have shown that DNase treatment impairs dendritic cell (DC) migration from the peritoneal cavity to the draining lymph node in mice immunized i.p. with alum. However, our data show that DNase does not affect accumulation of, or expression of costimulatory proteins on, antigen-loaded DCs in lymph nodes draining injected muscles, the site by which most human vaccines are administered. DNase does inhibit prolonged T-cell-DC conjugate formation and antigen presentation between antigen-positive DCs and antigen-specific CD4 T cells following i.m. injection. Thus, from the muscle, an immunization site that does not require host DNA to promote migration of inflammatory DCs, alum acts as an adjuvant by introducing host DNA into the cytoplasm of antigen-bearing DCs, where it engages receptors that promote MHC class II presentation and better DC-T-cell interactions.

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    • "However, the mechanism by which the host immune system initiates innate immune sensing of tumors and thereby bridges to induction of an adaptive tumorspecific T cell response is largely unknown. It has been suggested that endogenous adjuvants released from dying cells are capable of initiating innate immune cell activation (Jounai et al., 2012; Kono and Rock, 2008; Marichal et al., 2011; McKee et al., 2013). In chemotherapy and radiotherapy models, treated cancer cells were shown to release ATP or/and high-mobility group protein B1 (HMGB1) and activate dendritic cells (DCs) via the inflammasome or Toll-like receptor 4 (TLR4) pathways, respectively, which in turn contributed to activation of antitumor T cells (Apetoh et al., 2007; Ghiringhelli et al., 2009). "
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    ABSTRACT: Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 11/2014; 41(5):830-842. DOI:10.1016/j.immuni.2014.10.017 · 21.56 Impact Factor
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    • "Released host DNA is considered to be recognized by intracellular DNA sensors, but the detailed mechanisms by which the host DNA triggers the immune responses are unclear. Several reports have shown that stimulator of interferon genes (STING), interferon regulatory factor 3 (IRF3), and TANK-binding kinase 1 (TBK1), which are molecules associated with the signal pathway activated by host DNA, is required for the adjuvant activity of aluminum particle [74, 75]. "
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    Research Journal of Immunology 07/2014; 2014(2):962871. DOI:10.1155/2014/962871
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    • "Alum has been widely used as an adjuvant to boost immune responses, but the nature of its activition of DCs is poorly understood. Previous studies indicate that alum may activate DCs via inflammasome pathway [27], and/or in part promote DC maturation and antigen presentation by precipitating host DNA [28]. Percentages of BCL6hi cells in CD11c+ I-A+ cDCs were comparable before and after Alum immunization (Fig. 4A). "
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    ABSTRACT: The transcriptional repressor BCL6 plays an essential role in the development of germinal center B cells and follicular helper T cells. However, much less is known about the expression and function of BCL6 in other cell types. Here we report that during murine dendritic cell (DC) ontogeny in vivo, BCL6 is not expressed in bone marrow hematopoietic stem cells, common DC precursors and committed precursors of conventional DCs (pre-cDCs), but is elevated in peripheral pre-cDCs. BCL6 protein levels rise as pre-cDCs differentiate into cDCs in secondary lymphoid organs. Elevated protein levels of Bcl6 are observed in all cDC subsets, with CD8α+ cDCs displaying the greatest levels. Co-staining of Ki-67 revealed BCL6hi cDCs to be more proliferative than BCL6lo cDCs. After adjuvant inoculation, BCL6 levels are significantly reduced in the CD11cint MHC class IIhi CD86hi cDCs. Activation-induced BCL6 reduction correlated with reduced proliferation. A LPS injection study further confirmed that, in response to microbial stimuli, BCL6 levels are dynamically regulated during the maturation of CD11cint MHC class IIhi splenic cDCs. This reduction of BCL6 levels in cDCs does not occur after LPS injection in MyD88-/- TRIF-/- mice. Thus, regulation of Bcl6 protein levels is dynamic in murine cDCs during development, maturation and activation in vivo.
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