Translating viral vaccines into immunity

doi:10.1126/science.abf8121

GSTDTAP > 气候变化

DOI	10.1126/science.abf8121
	Translating viral vaccines into immunity
	Jennifer A. Juno; Shelby L. O'Connor
	2021-01-29
发表期刊	Science
出版年	2021
英文摘要	Viral vector–based vaccines use relatively harmless viruses as delivery vehicles of encoded antigens. Adenovirus vector–based vaccines are popular because they infect a wide variety of cell types, are replication incompetent, and use host cell machinery to produce the foreign protein. Understanding the mechanism by which adenovirus vector–based vaccines generate protective immunity to the expressed foreign antigen is essential for further developing this class of vaccines. On page 521 of this issue, Provine et al. ([ 1 ][1]) demonstrate that the generation of antigen-specific CD8+ T cells by adenovirus vector–based vaccines relies on mucosal-associated invariant T (MAIT) cells. Their data provide evidence that MAIT cells act as a link between the innate antiviral immune response and the generation of adaptive antiviral immunity for vaccines, such as the chimpanzee adenovirus Ox1 (ChAdOx1) nCoV-19 vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MAIT cells are innate-like T cells that sense foreign pathogens through at least two distinct mechanisms: T cell receptor (TCR)–dependent recognition of major histocompatibility complex (MHC) class I–related protein 1 (MR-1) molecules presenting vitamin B–derived metabolites on a range of antigen-presenting cells (APCs), and TCR-independent activation by cytokines produced during viral infection of APCs ([ 2 ][2]). Acute infections with influenza virus and dengue virus induce host APCs to produce cytokines, such as interleukin-18 (IL-18), IL-15, and type I interferons (IFNs), which activate MAIT cells ([ 2 ][2]–[ 4 ][3]). Acute HIV or simian immunodeficiency virus (SIV) infection also transiently promote s activation and proliferation of MAIT cells ([ 5 ][4]–[ 7 ][5]). These studies demonstrate that viral infections activate MAIT cells, but they do not explain whether MAIT cells subsequently boost the adaptive immune response. Adenovirus vectors have gained momentum as vaccines to elicit antigen-specific immunity against Ebola virus and SARS-CoV-2 ([ 8 ][6]–[ 10 ][7]). Two current SARS-CoV-2 vaccine vector candidates include the rare human adenovirus type Ad26 ([ 9 ][8], [ 11 ][9]) and the chimpanzee adenovirus vector ChAdOx1 ([ 10 ][7], [ 12 ][10]). These vaccines are particularly immunogenic because people lack preexisting neutralizing antibodies against these adenovirus serotypes ([ 13 ][11]). Vaccination with these vectors leads to cellular infection and expression of the foreign antigen. A rapid and robust innate immune response is then followed by the generation of T cells and antibodies specific for the foreign antigen ([ 9 ][8], [ 10 ][7]). ![Figure][12] Communicating vaccine immunogenicity Activation signals from adenoviral vector vaccines to CD8+ T cells occur through mucosal-associated invariant T (MAIT) cells. MAIT cells are activated by the cytokines [interferon-α (IFN-α), interleukin-18 (IL-18), and tumor necrosis factor (TNF)] produced after adenoviral infection of plasmacytoid dendritic cells (pDCs) and monocytes. These activated MAIT cells subsequently induce the expansion of vaccine antigen–specific CD8+ T cells by an unknown mechanism. GRAPHIC: V. ALTOUNIAN/ SCIENCE Provine et al. isolated specific cell subsets to show that ChAdOx1 virus particles infect plasmacytoid dendritic cells, which in turn produce type I IFN-α. The presence of IFN-α combined with concomitant adenoviral infection of monocytes causes the monocytes to produce IL-18 and tumor necrosis factor (TNF). Together, these three cytokines ultimately drive the activation of MAIT cells. Their activation was required to maximize the production of CD+ T cells specific for the vector-encoded foreign antigen: for example, the spike protein for the ChAdOx1 nCoV-19 vaccine (see the figure). They found that MR-1–deficient mice (which lack MAIT cells) produce fewer antigen-specific CD8+ T cells upon vaccination compared with wild-type mice. These data provide evidence that the purpose of viral sensing by MAIT cells is to improve the generation of antigen-specific CD8+ T cells elicited by chimpanzee adenoviral vaccine vectors. The observations of Provine et al. are expected to open the door to defining the mechanism by which MAIT cells subsequently promote the expansion of virus-specific CD8+ T cells. This will involve dissecting which MAIT cell–mediated signaling pathways are required to promote the development of antigen-specific CD8+ T cells. Understanding this mechanistic link will reveal fundamental communication mechanisms between innate and adaptive immune responses while also informing the design of future vaccines to maximally produce CD8+ T cells. High titers of antibodies specific for the spike protein are also elicited by the ChAdOx1 nCoV-19 vaccine, and data suggest that they correlate with protection ([ 10 ][7], [ 12 ][10], [ 14 ][13], [ 15 ][14]). Thus, a future study could explore whether chimpanzee adenoviral vaccines also prime MAIT cells to promote humoral immunity. This would include the production of antigen-specific CD4+ T cells and B cells that produce antibodies directed at a vaccine immunogen, such as the spike protein. Exploring whether the vaccinated wild-type mice produced higher titers of immunogen-specific antibodies when compared to MR-1–deficient mice would be an excellent follow-up experiment. It would also be exciting to learn whether the role of MAIT cells described by Provine et al. is required to protect the host from disease-causing pathogens. Demonstrating that vaccine-mediated induction of MAIT cells maximizes the production of antigen-specific CD8+ T cells only reflects vaccine immunogenicity. Whether MAIT cell activation positively correlates with the production of antibody and CD8+ T cells in vaccinated and protected macaques could complement the immunogenicity studies that Provine et al. carried out with wild-type and MR-1–deficient mice. Notably, macaque MAIT cell signaling and gene expression pathways were not explored, even though Provine et al. identified extensive similarities between these features of human and mouse MAIT cells. Macaques are valuable for studying the contributions of MAIT cells to lung immunity. They can be used to define whether adenoviral vector–based vaccines activate MAIT cells in the lungs, which may offer further insight into the immune correlates of protection from viruses, such as SARS-CoV-2. It is tempting to speculate whether adenovirus-induced MAIT cell activation could offer more generalized protection from viral infections whose antigens are not present in the vaccine. Without knowing the duration of MAIT cell activation or the mechanism by which MAIT cells induce the expansion of antigen-specific CD8+ T cells with these vaccines, it remains possible that MAIT cells have a nonspecific effect on augmenting antiviral immune responses systemically. The findings of Provine et al. further unravel the complex nature of MAIT cells as an integral link between the innate and adaptive arms of the immune system. MAIT cells were originally thought to be an essential component for protecting a host from bacterial infections, but their role in viral infections has become evident ([ 2 ][2]–[ 4 ][3]). Future studies will need to explore whether this role of MAIT cells is required to induce long-lasting protective immunity. 1. [↵][15]1. N. M. Provine et al ., Science 371, 521 (2021). [OpenUrl][16][Abstract/FREE Full Text][17] 2. [↵][18]1. J. E. Ussher, 2. C. B. Willberg, 3. P. Klenerman , Immunol. Cell Biol. 96, 630 (2018). [OpenUrl][19][CrossRef][20] 3. 1. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/314000
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Jennifer A. Juno,Shelby L. O'Connor. Translating viral vaccines into immunity[J]. Science,2021.
APA	Jennifer A. Juno,&Shelby L. O'Connor.(2021).Translating viral vaccines into immunity.Science.
MLA	Jennifer A. Juno,et al."Translating viral vaccines into immunity".Science (2021).