Single cell analysis uncovers novel populations of CD4+ T cells associated with antifungal vaccine efficacy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198466 | GEO | 2022/09/15
REPOSITORIES: GEO
Similar Datasets
Project description:HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in all vaccinated macaques following high-dose intravenous challenge by the pathogenic SHIVSF162P3CN. Poly-functional effector-memory CD8+ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8+ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8+ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.
2021-05-24 | GSE171783 | GEO
Project description:In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements likely depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory (Trm) T cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion or depletion, which may be harnessed to control liver infections or autoimmunity.
2016-10-02 | GSE71518 | GEO
Project description:Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection following disease resolution, effective immune protection has not yet been achieved by human vaccines. While circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFNγ, and remain resident in the skin when transplanted by skin graft onto naïve mice. They function to recruit circulating T cells to the skin in a CXCR3 dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells. Two conditions were analyzed. For each condition, four mice were used, resulting in eight samples in total.
2015-06-19 | E-GEOD-69998 | biostudies-arrayexpress
Project description:A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2 and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17 respectively. Here, we developed a new method to induce Tfh1, Tfh2 and Tfh17-like (iTfh1, iTfh2 and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.
2023-01-19 | GSE167309 | GEO
Project description:Recombinant adenoviral vectors (rAds), derived from distinct species with different serotypes, are lead vaccine candidates against Ebola, HIV, Tuberculosis and Malaria based on their potent induction of T cell immunity in humans. Importantly, rAds vary in their ability to induce protective cellular immunity. Here, the in vivo mechanisms controlling potency of CD8 T cell responses were assessed after vaccination with human-, chimpanzee- and simian-derived rAds encoding SIV-Gag. After rAd vaccination, we quantified antigen (Ag) expression and performed expression profiling of innate immune response genes in the draining lymph node. The most potent rAds (human-derived rAd5 and chimpanzee-derived chAd3) induced high and persistent Ag expression with low innate gene activation, while the less potent rAds exhibited reduced Ag expression with robust innate gene activation associated primarily with interferon (IFN) signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics, but did not alter memory responses or protection. Thus, the magnitude of memory CD8 T cell immune responses induced by rAds correlates with Ag expression but is independent of IFN and STING. These findings provide criteria for optimal induction of protective CD8 T cell immunity with rAd vaccines.
2014-12-30 | GSE64548 | GEO
Project description:The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ- modified mRNA (D1-modRNA), and m1Ψ-modified mRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an upregulation of Stat1 and RnaseL, and increased systemic inflammation. This correlated with a significantly reduced antigen specific antibody responses and reduced protection against influenza virus infection compared to D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material
2023-10-03 | E-MTAB-13194 | biostudies-arrayexpress
Project description:Parasitic nematodes of humans, animals and plants cause significant economic losses worldwide. Control of these pathogens is currently challenging due to the widespread problem of nematode anthelmintic resistance. Unfortunately, most efforts to develop anti-nematode vaccines for use in animals and humans have not succeeded. However, one effective (dead) anti-nematode vaccine (Barbervax) has been developed to protect livestock animals against the socioeconomically important parasitic nematode Haemonchus contortus (barber’s pole worm). This vaccine contains a major native antigen, termed H11. In its native form, H11 alone consistently induces high immunoprotection (75-95%) in animals, but recombinant forms thereof do not. Here, to test the hypothesis that post-translation modification of H11 is responsible for achieving the immunoprotection. We explored the N-glycoproteome and N-glycome of H11 using high-resolution mass spectrometry and assessed the roles of N-glycosylation in protective immunity against H. contortus. We demonstrated that N-glycans are a predominant protective component that induces protection and an associated IgG antibody response in immunised animals. We also showed that anti-H11 IgG antibodies confer specific, passive immunity in naïve animals. This study is the first detailed investigation of the relevance of protein glycosylation in protective immunity against a parasitic nematode, and should have important implications for developing vaccines against metazoan parasites.
2022-10-20 | PXD037140 | Pride
Project description:Enterotoxigenic Escherichia coli (ETEC) infections are a common cause of diarrheal illness in low- and middle-income countries. The live-attenuated ACE527 vaccine, adjuvanted with double mutant LT (dmLT), affords clear but partial protection against ETEC challenge inhuman volunteers. Comparatively, initial wild-type ETEC challenge completely protects against severe diarrhea on homologous re-challenge...To investigate molecular determinants of protection, vaccine antigen content was compared to wild-type ETEC, and proteome microarrays were used to assess immune responses following vaccination and ETEC challenge... Although molecular interrogation of the vaccine confirmed expression of targeted canonical antigens, relative to wild-type ETEC, vaccine strains were deficient in production of flagellar antigens, immotile, and lacked production of the EtpA adhesin. Similarly, vaccination ± dmLT elicited responses to targeted canonical antigens, but relative to wild-type challenge, vaccine responses to some potentially protective non-canonical antigens including EtpA were diminished or absent...These studies highlight important differences in vaccine and wild-type ETEC antigen content and call attention to distinct immunologic signatures that could inform investigation of correlates of protection, and guide vaccine antigen selection for these pathogens of global importance.
2019-07-25 | GSE134792 | GEO
Project description:The structural integrity of vaccine antigens is critical to the generation of protective antibody responses, but the impact of protease activity on vaccination in vivo is poorly understood. We characterized protease activity in lymph nodes and found that antigens were rapidly degraded in the subcapsular sinus, paracortex, and interfollicular regions, whereas low protease activity and antigen degradation rates were detected in the vicinity of follicular dendritic cells (FDCs). Correlated with these findings, immunization regimens designed to target antigen to FDCs led to germinal centers dominantly targeting intact antigen, whereas traditional immunizations led to much weaker responses that equally targeted the intact immunogen and antigen breakdown products. Thus, spatially compartmentalized antigen proteolysis affects humoral immunity and can be exploited.
2023-04-03 | GSE228809 | GEO
Project description:Inducing the long-term protection via effector memory CD8+ T cells residing in the peripheral tissues is the ultimate goal of T cell-based vaccination strategies. CD8+ T cell reacting against a particular set of antigenic peptides show propensity to generate stable pools of memory inflating cells with profound protective capacity. While the epitopes that induce memory inflation have been thoroughly characterized and used as excellent constituents of vaccines such as recombinant adenoviruses, the identity of the tissue factors responsible for maintaining memory inflating CD8+ T cells remains elusive. Here, we have used a Cre recombinase-dependent, -galactosidase (gal)–recombinant adenovirus vector that allowed for cell-specific expression of gal epitopes and identification of cell types involved in generation of inflationary responses. While targeting antigen expression to classical hematopoietic antigen presenting cells was insufficient to activate gal-specific CD8+ T cells, expressing the antigen exclusively in CCL19-producing fibroblastic stromal cells (FSCs) induced robust anti-gal CD8+ T cell response. Using bone marrow chimera mice to abolish the expression of major histocompatibility complex I (MHC-I) and Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3) in hematopoietic cells we demonstrated that CCL19-expressing FCS function as antigen libraries, gradually releasing the antigen to CD103+ DCs to maintain gal-specific memory inflating population. Moreover, targeted ablation of CCL19-producing cells revealed that pulmonary fibroblastic stromal cells act as the principal organizer of the nurturing niches that support the metabolic conversion in CD8+ T cells necessary for the generation of long-lasting protective inflationary responses. Overall, our data reveal a hitherto unknown function of CCL19-expressiong fibroblastic stromal in supporting the metabolic fitness of CD8+ T cells, thereby promoting the generation of tissue-specific and long-lasting protective CD8+ T cell responses.
2021-05-25 | E-MTAB-9558 | biostudies-arrayexpress