Biology subjects

van Duikeren, S.

Publications and source records attributed to van Duikeren, S..

3 recordsLinked to original sources

bioRxiv2021

OX40 agonism enhances efficacy of PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Immune checkpoint therapy (ICT) has the potency to eradicate cancer but the mechanisms that determine effective versus non-effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling we examined whether T cell states in the blood circulation could predict responsiveness to a combined ICT, sequentially targeting OX40 costimulatory and PD-1 inhibitory pathways, which effectively eradicated syngeneic mouse tumors. Unbiased assessment of transcriptomic alterations by single-cell RNA sequencing and profiling of cell-surface protein expression by mass cytometry revealed unique activation states for therapy-responsive CD4+ and CD8+ T cells. Effective ICT elicited T cells with dynamic expression of distinct NK cell and chemokine receptors, and these cells were systemically present in lymphoid tissues and in the tumor. Moreover, NK cell receptor-expressing CD8+ T cells were also present in the peripheral blood of immunotherapy-responsive cancer patients. Targeting of the NK cell and chemokine receptors in tumor-bearing mice showed their functional importance for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use of dynamic biomarkers on effector CD4+ and CD8+ T cells to improve cancer immunotherapy.

immunology↗

bioRxiv2021

A third vaccination with a single T cell epitope protects against SARS-CoV-2 infection in the absence of neutralizing antibodies

Understanding the mechanisms and impact of booster vaccinations can facilitate decisions on vaccination programmes. This study shows that three doses of the same synthetic peptide vaccine eliciting an exclusive CD8+ T cell response against one SARS-CoV-2 Spike epitope protected all mice against lethal SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model in the absence of neutralizing antibodies, while only a second vaccination with this T cell vaccine was insufficient to provide protection. The third vaccine dose of the single T cell epitope peptide resulted in superior generation of effector-memory T cells in the circulation and tissue-resident memory T (TRM) cells, and these tertiary vaccine-specific CD8+ T cells were characterized by enhanced polyfunctional cytokine production. Moreover, fate mapping showed that a substantial fraction of the tertiary effector-memory CD8+ T cells developed from remigrated TRM cells. Thus, repeated booster vaccinations quantitatively and qualitatively improve the CD8+ T cell response leading to protection against otherwise lethal SARS-CoV-2 infection. SummaryA third dose with a single T cell epitope-vaccine promotes a strong increase in tissue-resident memory CD8+ T cells and fully protects against SARS-CoV-2 infection, while single B cell epitope-eliciting vaccines are unable to provide protection.

immunology↗

bioRxiv2018

Off-target effects of Cre recombinase reveal limits of adoptive T cell transfers and persistent proliferation of effector CD8 T-cells

Effector-memory T-cells (TEM) are assumed to be short-lived cells that poorly proliferate upon antigenic restimulation, thus depending on central-memory T-cells (TCM) to replenish their numbers during homeostasis, largely depending on adoptive transfer evidence. Here we analyzed T cells in their natural environment and observed robust long-term in vivo cycling within the TEM subset that was stronger than the one in the TCM subset. Murine Cytomegalovirus (MCMV) induces inflationary TEM responses that remain high during latency. We analyzed Ki67 expression during acute and latent MCMV infection and found Ki67hiBcl2lo TEM in latently infected mice, arguing for antigen-driven TEM proliferation. TEM acquired deuterium more rapidly than TCM in an in vivo labeling experiment, and were replenished more rapidly than TCM after memory depletion, suggesting that TEM cycle faster than TCM. We depleted selectively the proliferating T-cells by Cre-overinduction, which resulted in a selective loss of Ki67hiBCl2lo effector T-cells, and an increase in the death of TEM in the spleen, while it hardly affected the TCM subset, arguing for robust proliferation of TEM in the spleen. On the other hand, TEM homing to the spleen upon adoptive transfer was substantially poorer than TCM, explaining the previously reported expansions of TCM, but not TEM, upon transfer. In conclusion, our data suggest that memory inflation is maintained by proliferation of antigen-specific TEM, rather than by continued expansion and differentiation of TCM.\n\nAuthor SummaryThe naive T cell population consists of T cells that have the potential to recognize millions of different pathogens. Upon infection, naive T cells that recognize the pathogen expand, and differentiate into effector T cells that eliminate infected cells. Once the infection is contained, the T cell pool contracts and only a small population of central memory T cells remains that can expand quickly upon re-infection. Cytomegaloviruses cause persistent infections that are not cleared from the organism after the initial immune response. In infected individuals a pool of CMV-specific effector memory T cells dominates the immune system in a phenomenon called memory inflation. Previous research using the transfer of central memory or effector memory T cells from CMV-infected mice into mice with a matching infection, showed expansion of central memory T cells but not effector memory T cells. Here we show that effector memory T cells have a reduced capacity to home into lymphoid organs, where T cell activation takes place, compared to central memory T cells. Using methods that do not interfere with T cell differentiation and homing, we show that effector memory T cells are proliferating during the persistent phase of CMV infection, significantly contributing to the upkeep of the inflationary population.

immunology↗