Dataset Information

MRNA vaccines engage unconventional pathways in CD8 T cell priming

ABSTRACT: Vaccines comprised of mRNA and lipid nanoparticles (LNP) activate B and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, activation of T cells requires antigen processing and presentation by MHC molecules on specialized antigen presenting cells (APCs). In response to viral infections, tumors and current vaccines, antigen presentation to CD8 T cells is particularly dependent on type 1 conventional dendritic cells (cDC1s) which are specialized for efficient antigen cross-presentation of exogenous antigens. However, whether similar mechanisms are employed by mRNA-LNP vaccination is currently unknown. Here, we show that mRNA LNP vaccines do not depend on cDC1 to induce CD8 T cell responses but engage cDC1 and cDC2 redundantly. In addition, these responses do not involve the normal WDFY4-dependent cross-presentation pathway. Rather, cDC2 are a prominent component driving CD8 T cells response against mRNA-LNP vaccination and engage cross-dressing of peptide-MHC-I complexes derived from non-hematopoietic cells. Notably, multimodal single cells analysis revealed that CD8 T cells primed either by cDC1 or cDC2 exhibit phenotypical differences. These results suggest that mRNA-LNP vaccination should be further evaluated for its ability to sustain normal functional memory that emerges from natural infections or vaccines that engage cDC1 for CD8 T cell priming.

ORGANISM(S): Mus musculus

PROVIDER: GSE296093 | GEO | 2026/02/15

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

Project description:Attenuated poxviruses are safe and capable to express foreign antigens. Poxviruses are applied in veterinary vaccination and explored as candidate vaccines for humans. However, poxviruses express multiple genes encoding proteins that interfere with components of the innate and adaptive immune response. This manuscript describes two strategies aimed to improve the immunogenicity of the highly attenuated, host-range restricted poxvirus NYVAC: deletion of the viral gene encoding type-I interferon-binding protein and development of attenuated replication-competent NYVAC. We evaluated these newly generated NYVAC mutants, encoding HIV-1 env, gag, pol and nef, for their ability to stimulate HIV-specific CD8 T-cell responses from blood mononuclear cells of HIV-infected subjects. The new vectors were evaluated and compared to the parental NYVAC vector in dendritic cells (DCs), RNA expression arrays, HIV gag expression and direct and cross-presentation assays in vitro. Deletion of type-I interferon-binding protein enhanced expression of interferon and interferon-induced genes in DCs, and increased maturation of infected DCs. Restoration of replication competence induced activation of pathways involving antigen processing and presentation. Also, replication-competent NYVAC showed increased Gag expression in infected cells, permitting enhanced cross-presentation to HIV-specific CD8 T cells and proliferation of HIV-specific memory CD8 T-cells. The recombinant NYVAC combining both modifications induced interferon-induced genes and genes involved in antigen processing and presentation, as well as increased Gag expression. This combined replication-competent NYVAC is a promising candidate for the next generation of HIV vaccines. RNA expression obtained from DCs infected by NYVAC-C-dB19R and NYVAC-C-KC-dB19R compared to RNA expression obtained from DCs infected by NYVAC-C Supplementary file 'normalized_data_Human_V3_V2.txt' reports data for ILMN identifiers common to platforms HumanRef8V2 and HumanRef8V3.

Dataset Information

MRNA vaccines engage unconventional pathways in CD8 T cell priming

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets