Biology subjects

Choudhuri, K.

Publications and source records attributed to Choudhuri, K..

3 recordsLinked to original sources

bioRxiv2025

T cell ectosomes promote antibody responses through cognate TCR-pMHC interactions

Protective antibody-mediated immunity requires effective T cell-mediated help. Recognition of peptide antigens presented by major histocompatibility complex class II molecules (pMHCII), via cognate T cell antigen receptors (TCR), activates CD4+ T helper cells to upregulate expression of CD40L and helper cytokines. CD40L-CD40 interactions at T-B cell synapses and secreted cytokines are well established mediators of T cell help. Whether engaged pMHCII also transmits signals that help B cells remains unresolved. Here, we show that TCR-enriched nanoscale vesicles shed by activated T cells (ectosomes) are transferred to antigen-primed B cells, where they engage and cluster cognate pMHCII, triggering signaling and specific IgG antibody production. Disruption of ectosome release attenuates B cell antibody production, while native and synthetic ectosomes boost antibody responses. We conclude that T cell ectosomes constitute a new modality of help for B cells, delivered through engagement of pMHCII by cognate ectosomal TCR.

immunology↗

bioRxiv2023

Membrane positioning across antigen-induced synaptic contacts tunes CAR-T cell signaling and effector responses

Tumor antigen recognition by chimeric antigen receptors (CAR) triggers phosphorylation of their cytoplasmic portions resulting in CAR-T cell activation. We and others have shown that immunoreceptor triggering depends on the formation of close synaptic contacts, determined by the span of immunoreceptor-ligand complexes, from which large inhibitory phosphatases such as CD45 are sterically excluded. Here, we show, varying CAR-antigen complex span, that CAR-T cell activation depends on a formation of close contacts with target cells. CAR-antigen complexes with a span of 4 immunoglobulin superfamily (IgSF) domains maximize CAR-T cell activation, closely matching the span of endogenous TCR-pMHC complexes. Longer CAR-antigen complexes precipitously reduced triggering and cytokine production, but notably, anti-tumor cytotoxicity was largely preserved due to a [~]10-fold lower signaling threshold for mobilization of cytolytic effector function. Increased intermembrane spacing disrupted short-spanned PD-1-PD- L1 interactions, reducing CAR-T cell exhaustion. Together, our results show that membrane positioning across the immunological synapse can be engineered to generate CAR-T cells with clinically desirable functional profiles in vitro and in vivo.

immunology↗

bioRxiv2023

Ligand-induced segregation from large cell-surface phosphatases is a critical step in γδ TCR triggering

Gamma/delta ({gamma}{delta}) T cells are unconventional adaptive lymphocytes that recognize structurally diverse ligands via somatically-recombined antigen receptors ({gamma}{delta} TCRs). The molecular mechanism by which ligand recognition initiates {gamma}{delta} TCR signaling, a process known as TCR triggering, remains elusive. Unlike {beta} TCRs, {gamma}{delta} TCRs are not mechanosensitive, and do not require coreceptors or typical binding-induced conformational changes for triggering. Here, we show that {gamma}{delta} TCR triggering by nonclassical MHC class Ib antigens, a major class of ligands recognized by {gamma}{delta} T cells, requires steric segregation of the large cell-surface phosphatases CD45 and CD148 from engaged TCRs at synaptic close contact zones. Increasing access of these inhibitory phosphatases to sites of TCR engagement, by elongating MHC class Ib ligands or truncating CD45/148 ectodomains, abrogates TCR triggering and T cell activation. Our results identify a critical step in {gamma}{delta} TCR triggering and provide insight into the core triggering mechanism of endogenous and synthetic tyrosine-phosphorylated immunoreceptors.

immunology↗