Biology subjects

Vigne, E.

Publications and source records attributed to Vigne, E..

3 recordsLinked to original sources

bioRxiv2023

Computational detection of antigen specific B cell receptors following immunization

B cell receptors (BCRs) play a crucial role in recognizing and fighting foreign antigens. High-throughput sequencing enables in-depth sampling of the BCRs repertoire after immunization. However, only a minor fraction of BCRs actively participate in any given infection. To what extent can we accurately identify antigen-specific sequences directly from BCRs repertoires? We present a computational method grounded on sequence similarity, aimed at identifying statistically significant responsive BCRs. This method leverages well-known characteristics of affinity maturation and expected diversity. We validate its effectiveness using longitudinally sampled human immune repertoire data following influenza vaccination and Sars-CoV-2 infections. We show that different lineages converge to the same responding CDR3, demonstrating convergent selection within an individual. The outcomes of this method hold promise for application in vaccine development, personalized medicine, and antibody-derived therapeutics.

immunology↗

bioRxiv2023

Targeting human γδ T cells as a potent and safe alternative to pan-T cells bispecific cell 2 engagers

Over the past decade, an increasing number of immunotherapies aiming to improve the ability of the immune system to effectively eradicate tumor cells have been developed. Among them, targeting effector T cell subsets of the immune system with bispecific antibodies, called T Cell Engagers (TCEs), represents an attractive strategy. TCEs are designed to specifically direct cytotoxic T cells towards tumor cells, thereby inducing a strong activation leading to the lysis of tumor cells. New strategies for targeting specific T-cell subsets are currently being explored. In this study, we investigated the activity of different TCEs on both conventional alpha beta ({beta}) T cells and unconventional gamma delta ({gamma}{delta}) T cells. We generated TCE molecules based on camelid single-domain antibodies (VHHs) that target the tumor-associated antigen CEACAM5 (CEA), together with particular T-cell receptor chains (TCRs) or a CD3 domain. The in vitro biological activity of the TCEs against the colon carcinoma cell line LS174T was measured using fresh and cultured human V{gamma}9V{delta}2 and {beta} T cells. We showed that V{gamma}9V{delta}2 T cells display stronger antitumor activity in vitro than {beta} T cells when activated with a CD3xCEA TCE. Furthermore, restricting T cell activation to V{gamma}9V{delta}2 T cells limits the production of pro-tumor factors and pro-inflammatory cytokines, which are often associated with toxicity in patients. Taken together, these results suggest that V{gamma}9V{delta}2{gamma}{delta} T cell-specific TCEs may represent safe, novel, specific, and effective molecules for improving antitumor immunotherapies.

immunology↗

bioRxiv2019

Structural basis of nanobody-recognition of grapevine fanleaf virus and of virus resistance loss

Grapevine fanleaf virus (GFLV) is a picorna-like plant virus transmitted by nematodes that affects vineyards worldwide. Nanobody (Nb)-mediated resistance against GFLV has been created recently and shown to be highly effective in plants including grapevine, but the underlying mechanism is unknown. Here we present the high-resolution cryo-EM structure of the GFLV-Nb23 complex which provides the basis for the molecular recognition by the nanobody. The structure reveals a composite binding site bridging over 3 domains of the capsid protein (CP) monomer. The structure provides a precise mapping of the Nb23 epitope on the GFLV capsid in which the antigen loop is accommodated through an induced fit mechanism. Moreover, we uncover and characterize several resistance-breaking GFLV isolates with amino acids mapping within this epitope, including C-terminal extensions of the CP, which would sterically interfere with Nb binding. Escape variants with such extended CP fail to be transmitted by nematodes linking Nb-mediated resistance to vector transmission. Together, these data provide insights into the molecular mechanism of Nb23-mediated recognition of GFLV and of virus resistance loss.\n\nSignificanceGrapevine fanleaf virus (GFLV) is a picorna-like plant virus that severely impacts vineyards worldwide. While Nanobodies (Nb) confer resistance to GFLV in plants the underlying molecular mechanism of action is unknown. Here we present the high-resolution cryo-EM structure of the GFLV-Nb complex. It uncovers the conformational epitope on the capsid surface which is a composite binding site into which the antigen loop is accommodated through an induced fit mechanism. Furthermore, we describe several resistance-breaking isolates of GFLV with reduced Nb binding capacity. Those that carry a C-terminal extension also fail to be transmitted by nematodes. Together, these data provide structure-function insights into the Nb-GFLV recognition and the molecular mechanism leading to loss of resistance.

biochemistry↗