Biology subjects

Abreu-Mota, T.

Publications and source records attributed to Abreu-Mota, T..

3 recordsLinked to original sources

bioRxiv2025

Non-cytolytic re-engineering of a viral vaccine vector enables durable effector-memory T cell immunity by reinforcing type I IFN induction

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. When comparing prototypic single-cycle vaccine delivery platforms we found that lymphocytic choriomeningitis virus-based vectors (rLCMV), which are non-cytolytic, elicited more durable and effector-memory-differentiated CD8 T cell responses than vectors based on cytolytic vesicular stomatitis virus (rVSV). Hence we re-engineered rVSV to be non-cytolytic (rVSVMq). This vector induced more durable and effector-differentiated CD8 T cell memory than the parental rVSV and it afforded superior protection against Listeria challenge. Improved CD8 T cell responses of non-cytolytic rVSVMq were driven by a reinforced type I interferon (IFN-I) response and its direct sensing by vaccination-induced CD8 T cells. Many vector cargo-specific CD8 T cells in the splenic marginal zone of rVSVMq- or rLCMV-vaccinated mice were in contact with vector cargo-expressing cells that co- expressed type I interferon. In contrast, rVSV-vectored cargo-expressing contacts of specific CD8 T cells were largely IFN type I-negative. Thereby, vaccination with non-cytolytic viral vectors offered an opportunity for CD8 T cells to integrate peptide-MHC and IFN-I signals during priming. These mechanistic insights should help to refine vaccines aimed at eliciting durable and protective effector- memory CD8 T cell immunity.

immunology↗

bioRxiv2025

Chronic Infection Perturbs the Affinity Hierarchy of Antiviral B Cells

The germinal center (GC) subjects antigen-specific B cells to a Darwinian selection process. Whether and how persistent viral infection perturbs the intended affinity hierarchy remains ill-defined. Here we transferred monoclonal lymphocytic choriomeningitis virus-specific B cells into persistently infected hosts. High affinity B cells expanded vigorously, forming GCs and abundant antibody-secreting cells. When failing to gain the upper hand over the virus, the expanded B cell population contracted, ending in its quasi-complete disappearance, a process termed "attrition". In stark contrast, low-affinity B cells expanded and persisted irrespective of high viral loads. B cell attrition was associated with phenotypic and transcriptional alterations including a prominent Blimp-1 transcriptional signature in high-affinity GC B cells. Blimp-1-deficient B cells were resistant to attrition, suggesting a B cell-intrinsic process. Moreover, exogenously supplied antibody feedback prevented attrition, indicating the latter resulted from excessive stimulation. Our findings reveal that in chronic viral infection the incessant activation by overwhelming amounts of antigen perturbs B cell affinity hierarchies by preferentially dysregulating high-affinity B cells.

immunology↗

bioRxiv2024

Permanent lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection

To interrogate the role of specific immune cells in infection, cancer and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods we engineer adeno-associated viral vectors expressing depletion-mAbs (depletion-AAVs). Single-dose depletion-AAV administration permanently eliminates lymphocyte subsets in mice while avoiding accessory deficiencies of GEMMs such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used irrespective of the animals genetic background, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we show that B cells are required for unimpaired CD4 and CD8 T cell responses to chronic viral infection. Importantly, CD8 T cells fail to suppress viremia when B cells are depleted, and they only help resolving chronic infection if antibodies suppress viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.

immunology↗