Article

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

ABSTRACT

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.

  • Source
    • "T-cell priming can be evaluated as a target for improving and modulating the immune response during vaccination [5], and as an early predictor of vaccine immunogenicity [6] [7]. CD4 + T-cell priming has been studied to characterize the mechanism of action of a broad range of adjuvants such as alum [8], CpG ODN [9], lipopolysaccharide [10], cholera toxin [11] or its B subunit (CTB) [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CD4(+) T-cell priming is an essential step in vaccination due to the key role of T helper cells in driving both effector and memory immune responses. Here we have characterized in C57BL/6 mice the T helper subtype differentiation among tetramer-specific CD4(+) T cells primed by subcutaneous immunization with the tuberculosis vaccine antigen H56 plus the adjuvant CAF01. Peptide-specific population identified by the MHC class II tetramers differentiated into several T helper subtypes upon antigen encounter, and the frequency of subpopulations differed according to their localization. Th1 (CXCR3(+)T-bet(+)), Tfh (CXCR5(+)PD-1(+)Bcl-6(+)) and RORγt(+) cells were induced in the lymph nodes draining the immunization site (dLN), while Th1 cells were the predominant subtype in the spleen. In addition, CD4(+) T cells co-expressing multiple T-cell lineage-specifying transcription factors were also detected. In the lungs, most of the tetramer-binding T cells were RORγt(+), while Tfh and Th1 cells were absent. After boosting, a higher frequency of tetramer-binding cells co-expressing the markers CD44 and CD127 was detected compared to primed cells, and Tet(+) T cells showed a prevalent Th1 phenotype in both dLN and spleens, while Tfh cells were significantly reduced. In conclusion, these data demonstrate that parenteral immunization with H56 and CAF01 elicits a distribution of antigen-specific CD4(+) T cells in both lymphoid tissues and lungs, and gives rise to multiple T helper subtypes, that differ depending on localization and following reactivation.
    Full-text · Article · Oct 2015 · Vaccine
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2014 · Immunity
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary inflammation, especially persistent inflammation, has been found to play a key role in respiratory disorders induced by nanoparticles in animal models. In inhalation studies and instillation studies of nanomaterials, persistent inflammation is composed of neutrophils and alveolar macrophages, and its pathogenesis is related to chemokines such as the cytokine-induced neutrophil chemoattractant (CINC) family and macrophage inflammatory protein-1 α and oxidant stress-related genes such as heme oxygenase-1 (HO-1). DNA damages occur chemically or physically by nanomaterials. Chemical and physical damage are associated with point mutation by free radicals and double strand brake, respectively. The failure of DNA repair and accumulation of mutations might occur when inflammation is prolonged, and finally normal cells could become malignant. These free radicals can not only damage cells but also induce signaling molecules containing immunoreaction. Nanoparticles and asbestos also induce the production of free radicals. In allergic responses, nanoparticles act as Th2 adjuvants to activate Th2 immune responses such as activation of eosinophil and induction of IgE. Taken together, the presence of persistent inflammation may contribute to the pathogenesis of a variety of diseases induced by nanomaterials.
    Full-text · Article · Jul 2014 · Research Journal of Immunology
Show more