TCR Transgenic Mice: A Valuable Tool for Studying Viral Immunopathogenesis Mechanisms

Cho, Yong-Bin; Lee, In-Gu; Joo, Yong-Hyun; Hong, Seok Il; Seo, Young-­Jin

doi:10.3390/ijms21249690

Cited by 10 publications

(7 citation statements)

References 104 publications

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“…The discovery of the chain-centricity phenomenon of some TCRs may have a substantial impact on TCR gene editing applications. For the generation of transgenic animals, the transgenesis of a single dominant active α-chain could produce animals with improved immunity without the significant alterations of the native TCR repertoire that occurs with the transgenesis of β-chains [ 17 , 18 ] or fully rearranged TCRs [ 19 ]. Our studies confirmed that this experimental approach can be used for the generation of transgenic animals with inheritable advanced anti-tumor immune defenses [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Physiological and Functional Effects of Dominant Active TCRα Expression in Transgenic Mice

Kalinina

Ziganshin

Silaeva

et al. 2023

IJMS

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A T cell receptor (TCR) consists of α- and β-chains. Accumulating evidence suggests that some TCRs possess chain centricity, i.e., either of the hemi-chains can dominate in antigen recognition and dictate the TCR’s specificity. The introduction of TCRα/β into naive lymphocytes generates antigen-specific T cells that are ready to perform their functions. Transgenesis of the dominant active TCRα creates transgenic animals with improved anti-tumor immune control, and adoptive immunotherapy with TCRα-transduced T cells provides resistance to infections. However, the potential detrimental effects of the dominant hemi-chain TCR’s expression in transgenic animals have not been well investigated. Here, we analyzed, in detail, the functional status of the immune system of recently generated 1D1a transgenic mice expressing the dominant active TCRα specific to the H2-Kb molecule. In their age dynamics, neither autoimmunity due to the random pairing of transgenic TCRα with endogenous TCRβ variants nor significant disturbances in systemic homeostasis were detected in these mice. Although the specific immune response was considerably enhanced in 1D1a mice, responses to third-party alloantigens were not compromised, indicating that the expression of dominant active TCRα did not limit immune reactivity in transgenic mice. Our data suggest that TCRα transgene expression could delay thymic involution and maintain TCRβ repertoire diversity in old transgenic mice. The detected changes in the systemic homeostasis in 1D1a transgenic mice, which are minor and primarily transient, may indicate variations in the ontogeny of wild-type and transgenic mouse lines.

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Section: Discussionmentioning

confidence: 99%

Physiological and Functional Effects of Dominant Active TCRα Expression in Transgenic Mice

Kalinina

Ziganshin

Silaeva

et al. 2023

IJMS

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“…One of the key features of adaptive immunity is the enormous receptor diversity of lymphocytes, which is estimated to cover over 10 10 unique sequences for T cells alone ((Cho et al, 2020; Lythe et al, 2016). This empowers the adaptive immune system to tackle an infinite number of invaders.…”

Section: Introductionmentioning

confidence: 99%

TCR transgenic clone selection guided by immune receptor analysis and single cell RNA expression of polyclonal responders

Debeuf,

Lameire,

Vanheerswynghels

et al. 2024

Preprint

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Since the precursor frequency of naive T cells is extremely low, investigating the early steps of antigen-specific T cell activation is challenging. To overcome this detection problem, adoptive transfer of a cohort of T cells purified from T cell receptor (TCR) transgenic donors has been extensively used but is not readily available for emerging pathogens. Constructing TCR transgenic mice from T cell hybridomas is a labor-intensive and sometimes erratic process, since the best clones are selected based on antigen-induced CD69 upregulation or IL-2 production in vitro, and TCR chains are PCR-cloned into expression vectors. Here, we exploited the rapid advances in single cell sequencing and TCR repertoire analysis to select the best clones without hybridoma selection, and generated CORSET8 mice (CORona Spike Epitope specific CD8 T cell), carrying a TCR specific for the Spike protein of SARS-CoV-2. Implementing newly created DALI software for TCR repertoire analysis in single cell analysis enabled the rapid selection of the ideal responder CD8 T cell clone, based on antigen reactivity, proliferation and immunophenotype in vivo. In contrast, a traditional method based on hybridoma technology was unsuccessful. Identified TCR sequences were inserted as synthetic DNA into an expression vector and transgenic CORSET8 donor mice were created. After immunization with Spike/CpG-motifs, mRNA vaccination or SARS-CoV2 infection, CORSET8 T cells strongly proliferated and showed signs of T cell activation. Thus, a combination of TCR repertoire analysis and scRNA immunophenotyping allowed rapid selection of antigen-specific TCR sequences that can be used to generate TCR transgenic mice.

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“…In the fever phase, it was significantly elevated [4]. In addition, the diversity of T and B cell receptors is of great significance for the research and treatment of infectious diseases [5,6]. However, the diversity characteristics of TCR and BCR in HFRS remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Single cells and TRUST4 reveal immunological features of the HFRS transcriptome

Xiao,

Lin,

liu

et al. 2023

Preprint

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The pathogenesis of hemorrhagic fever with renal syndrome (HFRS) is greatly affected by different immune cells. At present, peripheral blood T cell receptor (TCR) or B cell receptor (BCR) library sequencing of HFRS is still lacking and expensive. In this study, the computational method TRUST4 was used to construct TCR and BCR libraries from a large number of RNA-seq data of peripheral blood of HFRS patients, and to analyze the clonality and diversity of disease immune libraries. Although the function of immune cells has been studied, the mechanism remains complex. The differentially expressed genes in each immune cell type and the cell-to-cell interactions between immune cell clusters have not been covered. In this work, we clustered 11 cell subsets from raw scRNA-seq data and disaggregated the characteristic changes in the proportion of cell subsets under disease conditions. CellChat, a cell-cell communication analysis tool, was also used to analyze the effects of MIF family, CD70 family, and GALECTIN family cytokines, which are reported to be involved in cell communication subsets, respectively. HDWGCNA analysis identified core genes involved in the occurrence and development of HFRS in T cells and B cells. The results of trajectory analysis showed that most cell subsets were in the developmental stage, transcription factors in Effector CD8+ T cells (GZMH), Effector CD8+ T cells (GZMK), It was highly expressed in Naive CD4+ T cells and Naive B cells. Our results comprehensively illustrated the dynamic changes of immune cells during the pathogenesis of HFRS. This work identifies specific V genes and J genes in TCR and BCR that can be used to extend our understanding of HFRS. These findings provide new insights into the diagnosis and treatment of this autoimmune disease.

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TCR Transgenic Mice: A Valuable Tool for Studying Viral Immunopathogenesis Mechanisms

Cited by 10 publications

References 104 publications

Physiological and Functional Effects of Dominant Active TCRα Expression in Transgenic Mice

Physiological and Functional Effects of Dominant Active TCRα Expression in Transgenic Mice

TCR transgenic clone selection guided by immune receptor analysis and single cell RNA expression of polyclonal responders

Single cells and TRUST4 reveal immunological features of the HFRS transcriptome

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