Biology subjects

Bustamante Eguiguren, S.

Publications and source records attributed to Bustamante Eguiguren, S..

3 recordsLinked to original sources

bioRxiv2025

Optimising CAR-T cell sensitivity by engineering matched extracellular sizes between CAR/antigen and CD2/CD58 adhesion complexes

Chimeric antigen receptor (CAR)-T cells exhibit low antigen sensitivity, which restricts their therapeutic efficacy and leads to patient relapses when cancer cells downregulate antigen expression. Despite the pressing need to overcome this limitation, the underlying mechanisms remain poorly understood. Here, we demonstrate that enhancing CAR sensitivity to match the sensitivity of the T-cell receptor (TCR) can be achieved by engineering matched extracellular sizes of CAR/antigen and CD2/CD58 complexes. We find that different CAR/antigen sizes, which are generated by different CAR architectures and different target antigens, require a different CD2/CD58 size to optimise sensitivity. This extracellular size-matching improves antigen engagement and co-localisation of CAR/antigen and CD2/CD58 complexes. We also find that size-matching controls co-inhibition of CARs by PD-1/PD-L1. These findngs highlight the importance of size-matching for signal integration by surface receptors and offers a new approach to tune CAR-T cell sensitivity by matching or mismatching extracellular sizes. One sentence summaryThe antigen sensitivity of CAR-T cells can be tuned to match the sensitivity of TCR-T cells by varying the relative extracellular size of CAR/antigen and CD2/CD58 complexes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/631424v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@17e6a55org.highwire.dtl.DTLVardef@771b38org.highwire.dtl.DTLVardef@19c3544org.highwire.dtl.DTLVardef@6d1fe1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Using CombiCells, a platform enabling titration and combinatorial display of cell surface ligands, to investigate the sensitivity and costimulatory requirements of TCRs and CARs

Understanding how cellular decisions by receptor/ligand interactions at cell/cell interface has been challenging because it is difficult to independently vary the surface density of multiple ligands. Here, we exploit the SpyCatcher/SpyTag split-protein system for rapid combinatorial display of native ligands on cells (Combicells). We use this platform to assess T cell antigen sensitivity and the impact of T cell co-stimulation/co-inhibition receptors. The TCR displayed much greater sensitivity to pMHC than CARs and BiTES did to CD19. While TCR sensitivity was greatly enhanced by CD2 ligand, CAR sensitivity to CD19 was primarily but more modestly enhanced by LFA-1 ligand. Lastly, we show that the PD-1/ligand engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor/ligand interactions at cell/cell interfaces. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/545075v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@d1ec95org.highwire.dtl.DTLVardef@33c0forg.highwire.dtl.DTLVardef@5bfed7org.highwire.dtl.DTLVardef@1b80ee2_HPS_FORMAT_FIGEXP M_FIG C_FIG One sentence summaryUsing CombiCells, a platform for the combinatorial display of cell surface ligands, to compare T cell antigen sensitivity mediated by TCRs, CARs, and BiTEs and its dependence on co-stimulation/co-inhibition receptor ligands

immunology↗

bioRxiv2019

Convergence of glandular trichome morphology and chemistry in two montane monkeyflower species

Two distantly-related North American montane monkeyflower species, Mimulus lewisii and Mimulus tilingii, possess glandular trichomes. In this study, we characterized the morphological and histochemical features of these glandular trichomes. For each species, we used traditional light microscopy and scanning electron microscopy (SEM) to examine morphological characteristics, and determined the main components of the secretory products using histochemical and thin layer chromatography (TLC) staining techniques. We identified type VI glandular trichomes on leaf surfaces in both species of monkeyflowers. These trichomes exhibited stalk-cell lengths and head-cell counts that varied across adaxial and abaxial leaf surfaces, stems, and sepals. Both species contained secretory products within the cuticle of the trichome head, which releases the subcuticular metabolites when ruptured. Histochemical tests in both M. lewisii and M. tilingii confirmed that secretions contained lipids and polysaccharides. TLC plate staining indicated the presence of UV active compounds with polyalcohols, lipids, and amines. The common morphology and chemistry of the glandular trichomes suggests an analogous response to similar environmental conditions in these evolutionary distant montane monkeyflowers.

plant biology↗