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Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon [scRNA-Seq]

ABSTRACT: Replication-deficient viral vector systems hold promise for CD8 T cell-based vaccination, but the molecular mechanisms accounting for platform-specific differences in immunogenicity remain ill-defined. Here we compared lymphocytic choriomeningitis virus- (rLCMV) and vesicular stomatitis virus-based (rVSV) single-cycle vectors to explore vector-specific features determining long-lived effector-memory CD8 T cell induction. rLCMV, a non-cytolytic vector, elicited more durable CD8 T cell responses and a higher proportion of effector-memory CD8 T cells than cytolytic rVSV. When rVSV was re-engineered to be non-cytolytic (rVSVMq), also this vector induced durable and effector-differentiated CD8 T cell memory, reminiscent of rLCMV-induced responses, and it afforded superior protection against Listeria challenge than rVSV. Improved CD8 T cell responses of non-cytolytic rVSVMq depended on an elevated type I interferon (IFN-I) response and its direct sensing by vaccination-induced CD8 T cells. Many rVSVMq-infected cells in the splenic marginal zone that were in contact with antigen-specific CD8 T cells expressed not only vectorized antigen but also IFN-I, suggesting that non-cytolytic viral vectors promote the integration of peptide-MHC and IFN-I signals during T cell activation. These mechanistic insights should help to refine vaccines aimed at eliciting durable and protective effector-memory CD8 T cell immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE317029 | GEO | 2026/02/25

REPOSITORIES: GEO

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Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon [TCR-Seq]

Project description:Replication-deficient viral vector systems hold promise for CD8 T cell-based vaccination, but the molecular mechanisms accounting for platform-specific differences in immunogenicity remain ill-defined. Here we compared lymphocytic choriomeningitis virus- (rLCMV) and vesicular stomatitis virus-based (rVSV) single-cycle vectors to explore vector-specific features determining long-lived effector-memory CD8 T cell induction. rLCMV, a non-cytolytic vector, elicited more durable CD8 T cell responses and a higher proportion of effector-memory CD8 T cells than cytolytic rVSV. When rVSV was re-engineered to be non-cytolytic (rVSVMq), also this vector induced durable and effector-differentiated CD8 T cell memory, reminiscent of rLCMV-induced responses, and it afforded superior protection against Listeria challenge than rVSV. Improved CD8 T cell responses of non-cytolytic rVSVMq depended on an elevated type I interferon (IFN-I) response and its direct sensing by vaccination-induced CD8 T cells. Many rVSVMq-infected cells in the splenic marginal zone that were in contact with antigen-specific CD8 T cells expressed not only vectorized antigen but also IFN-I, suggesting that non-cytolytic viral vectors promote the integration of peptide-MHC and IFN-I signals during T cell activation. These mechanistic insights should help to refine vaccines aimed at eliciting durable and protective effector-memory CD8 T cell immunity.

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Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon

Project description:Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon

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Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon [scRNA-Seq]

Project description:Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon [scRNA-Seq]

| PRJNA1405688 | ENA

Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon [TCR-Seq]

Project description:Non-cytolytic viral vaccine vectors induce durable effector-memory CD8 T cell immunity by triggering type I interferon [TCR-Seq]

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Gene expression profiles of human CD8+ T cells: IL-12 and IFN-a polarized in vitro stimulated and ex vivo sorted CCR7hi and CXCR3hi populations

Project description:CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. While effector CTLs eliminate the infection, a small population of memory cells are retained that yields more rapid and robust response upon re-infection. Antigen presenting cells secrete an array of innate cytokines including IL-12 and IFN-α after recognition of pathogens. Both IL-12 and IFN-α have been shown to act as the third signal regulating the development of CTLs. We have shown that these two cytokines have a non-redundant effect in generation of human effector CTL. IL-12 alone is sufficient for effector CTL genesis marked by IFN-γ and TNF-α production, as well as increased cytolytic activity. Even in the presence of IFN-α, IL-12 programs CTLs that express the chemokine receptor CXCR3 and effector cytokines. Using microarray analysis we have investigated how IL-12 and IFN-α differentially regulate the genetic programming pathways that give rise to effector CTLs among multiple human donors. We have also analyzed the gene expression patterns of cells sorted from healthy human peripheral blood that display surface markers of effector memory CTL (designated as ex vivo) samples. 5 healthy human donor samples were used for the in vitro cultures. For each donor the CFSE labeled cells (CD8+CD45RA+) were cultured in the presence of neutralized, IL-12, IFN-a, and IL-12+IFN-a conditions and plate-bound anti-CD3+anti-CD28 for 3.5 days. Total RNA from CFSEhi (Undiv) and CFSElo (Div) sorted cells were used for Illumina Bead Array. 4 healthy human donor samples were used for the ex vivo samples. Total RNA was collected from FACS sorted CD8+CCR7hiCXCR3lo and CD8+CCR7loCXCR3hi cells without any stimulation.

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Project description:Recombinant vesicular stomatitis virus (rVSV) is a promising viral vaccine vector for addressing the COVID-19 pandemic. Inducing mucosal immunity via the intranasal route is an ideal strategy for rVSV-based vaccines, but it requires extremely stringent safety standards. In this study, we constructed two rVSV variants with amino acid mutations in their M protein: rVSV-M2 with M33A/M51R mutations and rVSV-M4 with M33A/M51R/V221F/S226R mutations, and developed COVID-19 vaccines based on these attenuated vectors. By comparing viral replication capacity, intranasal immunization, intracranial injection, and blood cell counts, we demonstrated that the M protein mutation variants exhibit significant attenuation effects both in vitro and in vivo. Moreover, preliminary investigations into the mechanisms of virus attenuation revealed that these attenuated viruses can induce a stronger type I interferon response while reducing inflammation compared to the wild-type rVSV. We developed three candidate vaccines against SARS-CoV-2 using wild-type rVSV (rVSV-JN.1) and the two variants (rVSV-M2-JN.1 and rVSV-M4-JN.1). Our results confirmed that rVSV-M2-JN.1 and rVSV-M4-JN.1 retain strong immunogenicity while enhancing safety in hamsters. In summary, the rVSV variants with M protein mutations represent promising candidate vectors for mucosal vaccines and warrant further investigation.

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2015-09-23 | E-GEOD-73314 | biostudies-arrayexpress

Super-killer CTLs are generated by single gene deletion of Bach2

Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.

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