Dataset Information

Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8⁺ T cell detection.

ABSTRACT: Peptide-MHC (pMHC) multimers have excelled in the detection of antigen-specific T cells and have allowed phenotypic analysis using other reagents, but their use for detection of low-affinity T cells remains a challenge. Here we develop a multimeric T cell identifying reagent platform using two-dimensional DNA origami scaffolds to spatially organize pMHCs (termed as dorimers) with nanoscale control. We show that these dorimers enhance the binding avidity for low-affinity antigen-specific T cell receptors (TCRs). The dorimers are able to detect more antigen-specific T cells in mouse CD8⁺ T cells and early-stage CD4⁺CD8⁺ double-positive thymocytes that express less dense TCRs, compared with the equivalent tetramers and dextramers. Moreover, we demonstrate dorimer function in the analysis of autoimmune CD8⁺ T cells that express low-affinity TCRs, which are difficult to detect using tetramers. We anticipate that dorimers could contribute to the investigation of antigen-specific T cells in immune T cell function or immunotherapy applications.

SUBMITTER: Sun Y

PROVIDER: S-EPMC9263106 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8<sup>+</sup> T cell detection.

Sun Yueyang Y Yan Lu L Sun Jiajia J Xiao Mingshu M Lai Wei W Song Guangqi G Li Li L Fan Chunhai C Pei Hao H

Nature communications 20220707 1

Peptide-MHC (pMHC) multimers have excelled in the detection of antigen-specific T cells and have allowed phenotypic analysis using other reagents, but their use for detection of low-affinity T cells remains a challenge. Here we develop a multimeric T cell identifying reagent platform using two-dimensional DNA origami scaffolds to spatially organize pMHCs (termed as dorimers) with nanoscale control. We show that these dorimers enhance the binding avidity for low-affinity antigen-specific T cell r ...[more]

PMID: 35798752

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Project description:BackgroundTumor necrosis factor receptor superfamily 25 (TNFRSF25) is a T-cell co-stimulatory receptor. Expression of its ligand, TNF-like cytokine 1A (TL1A), on mouse tumor cells has been shown to promote tumor regression. This study aimed to develop TNFRSF25 agonists (both antibodies (Abs) and TL1A proteins) and to investigate their potential antitumor effects.MethodsAnti-mouse TNFRSF25 (mTNFRSF25) Abs and multimeric TL1A proteins were generated as TNFRSF25 agonists. Their agonism was assessed in luciferase reporter and T-cell co-stimulation assays, and their antitumor effects were evaluated in syngeneic mouse tumor models. TNFRSF25 expression within the tumor microenvironment and the effects of an anti-mTNFRSF25 agonistic Ab on tumor-infiltrating T cells were evaluated by flow cytometry. Cell depletion assays were used to identify the immune cell types that contribute to the antitumor effect of the anti-mTNFRSF25 Ab. The Fc gamma receptor (FcγR) dependence of TNFRSF25 agonists was assessed in an in vivo T-cell expansion model and a mouse tumor model using Fc variants and FcγR-deficient mice.ResultsTNFRSF25 agonists exhibited antitumor effects in syngeneic mouse tumor models without causing observed side effects. We identified an anti-mTNFRSF25 agonistic Ab, 1A6-m1, which exhibited greater antitumor activity than a higher affinity anti-TNFRSF25 Ab which engages an overlapping epitope with 1A6-m1. 1A6-m1 activated CD8+ T cells and antigen-specific T cells, leading to tumor regression; it also induced long-term antitumor immune memory. Although activating TNFRSF25 by 1A6-m1 expanded splenic regulatory T (Treg) cells, it did not influence intratumoral Treg cells. Moreover, 1A6-m1's antitumor effects required the engagement of both inhibitory FcγRIIB and activating FcγRIII. Replacing 1A6-m1's CH1-hinge region with that of human IgG2 (h2) conferred enhanced antitumor effects. Finally, we also generated multimeric human and mouse TL1A fusion proteins as TNFRSF25 agonists, and they co-stimulated CD8+ T cells and reduced tumor growth, even in the absence of Fc-FcγR interactions.ConclusionOur data demonstrates the potential of activating TNFRSF25 by Abs and multimeric TL1A proteins for cancer immunotherapy and provides insights into their development astherapeutics.

Dataset Information

Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8⁺ T cell detection.

Publications

Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8<sup>+</sup> T cell detection.

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Dataset Information

Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8+ T cell detection.

Publications

Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8<sup>+</sup> T cell detection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Nanoscale organization of two-dimensional multimeric pMHC reagents with DNA origami for CD8⁺ T cell detection.