Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells

ArticleinProceedings of the National Academy of Sciences 110(12) · February 2013with19 Reads
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.
    • "0.05). (3) showed that the adjuvant effects of alum were reduced in mice lacking STING (3) or its downstream, signaling partners Tbk1 and Irf3 (2). In our hands, the reduction caused by lack of STING was much less than that caused by DNase. "
    [Show abstract] [Hide abstract] ABSTRACT: Aluminum salt (alum) adjuvants have been used for many years as adjuvants for human vaccines because they are safe and effective. Despite its widespread use, the means by which alum acts as an adjuvant remains poorly understood. Recently, it was shown that injected alum is rapidly coated with host chromatin within mice. Experiments suggested that the host DNA in the coating chromatin contributed to alum's adjuvant activity. Some of the experiments used commercially purchased DNase and showed that coinjection of these DNase preparations with alum and Ag reduced the host's immune response to the vaccine. In this study, we report that some commercial DNase preparations are contaminated with proteases. These proteases are responsible for most of the ability of DNase preparations to inhibit alum's adjuvant activity. Nevertheless, DNase somewhat reduces responses to some Ags with alum. The effect of DNase is independent of its ability to cleave DNA, suggesting that alum improves CD4 responses to Ag via a pathway other than host DNA sensing.
    Article · Jun 2016
    • "The latter groups found that DNase inhibited prolonged Ag presentation and DC-T cell interactions after i.m. injection in these mice. Thus demonstrating that host DNA introduced into the cytoplasm with the activation of STING pathway of Ag-bearing DCs enhanced p:MHCII presentation and DC-T cell interactions (McKee et al. 2013). Other factors such as histone proteins may be involved in alum mediated innate immune responses (Munks et al. 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Adjuvants such as the aluminum compounds (alum) have been dominantly used in many vaccines due to their immunopotentiation and safety records since 1920s. However, how these mineral agents influence the immune response to vaccination remains elusive. Many hypotheses exist as to the mode of action of these adjuvants, such as depot formation, antigen (Ag) targeting, and the induction of inflammation. These hypotheses are based on many in vitro and few in vivo studies. Understanding how cells interact with adjuvants in vivo will be crucial to fully understanding the mechanisms of action of these adjuvants. Interestingly, how alum influences the target cell at both the cellular and molecular level, and the consequent innate and adaptive responses, will be critical in the rational design of effective vaccines against many diseases. Thus, in this review, mechanisms of action of alum have been discussed based on available in vitro vs in vivo evidences to date.
    Full-text · Article · Dec 2015
    • "However, there is disagreement about the necessity of this pro-inflammatory response pathway in generating adjuvant effects in vivo [14], with NLRP3-deficient mice mounting a normal OVA-specific IgG 1 response [15]. Studies have demonstrated that aluminum hydroxide could induce cytotoxicity and host DNA release at sites of immunization [16, 17], which mediate the adjuvant effect for Th2-biased adaptive immune responses (Fig. 1). In addition, it has been shown that aluminum adjuvants are able to perturb the DC membrane as a way of providing immune stimulation [18] . "
    Full-text · Chapter · Jan 2015 · SpringerPlus
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