Annals of the rheumatic diseases · 2026
A new humanised TCR transgenic mouse model to study T cells reactive to citrullinated tenascin C, a relevant autoantigen in rheumatoid arthritis.
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Schülein Marlene, Afonso Marcelo, Sijbranda Merel, Pulgarin Diego Velasquez, Dubnovitsky Anatoly, Hansson Monika, Réthi Bence, Wermeling Fredrik, Winkler Aaron, Klareskog Lars, Espinosa Alexander, Malmström Vivianne, Raposo Bruno
Аннотация
OBJECTIVES: Autoreactive T cells recognising citrullinated antigens, although rare and difficult to study, are implicated in rheumatoid arthritis (RA). To allow functional studies and manipulation of such T cells, we have generated and characterised transgenic mice expressing a T-cell receptor (TCR) cloned from a patient with RA and reactive with a prominent target, citrullinated tenascin C (citTNC).
METHODS: A humanised TCR transgenic (hTCR-tg) mouse recognising the citrullinated tenascin C22 (citTNC22) antigen in an HLA-DRB1*04:01 (HLA-DR4) restricted manner was developed by genetically engineering a chimeric TCR expressing murine constant domains and human V(D)J sequences. hTCR-tg mice were immune phenotyped in murine H-2b and humanised HLA-DR4 backgrounds using full-spectrum flow cytometry, cytokine enzyme-linked immunosorbent assays, and Fluorospot assays at steady state and after antigen challenge. Additionally, we investigated the presence of antibodies to citTNC and arthritis after citTNC protein immunisation.
RESULTS: Thymic selection of hTCR T cells differed between the 2 major histocompatibility complex class II alleles, with normal CD4+ T-cell development observed solely under HLA-DR4 restriction. The chimeric hTCR maintained its citTNC22 specificity in vitro and ex vivo, without cross-reactivity to native TNC22 or other citrullinated autoantigens. hTCR-tg CD4+ T cells responded to antigen challenge in vivo and provided support to IgG class-switch and antigen-specific antibody production. Moreover, protein-immunised hTCR-tg mice developed arthritis after periarticular challenge with citTNC.
CONCLUSIONS: hTCR-tg mice expressing an RA patient-derived autoreactive TCR develop functional antigen-specific and HLA-restricted CD4+ T cells. The combination of humanised HLA-DR4 and TNC22 mice will be a valuable tool in the development of antigen-specific therapies translatable to human disease.
METHODS: A humanised TCR transgenic (hTCR-tg) mouse recognising the citrullinated tenascin C22 (citTNC22) antigen in an HLA-DRB1*04:01 (HLA-DR4) restricted manner was developed by genetically engineering a chimeric TCR expressing murine constant domains and human V(D)J sequences. hTCR-tg mice were immune phenotyped in murine H-2b and humanised HLA-DR4 backgrounds using full-spectrum flow cytometry, cytokine enzyme-linked immunosorbent assays, and Fluorospot assays at steady state and after antigen challenge. Additionally, we investigated the presence of antibodies to citTNC and arthritis after citTNC protein immunisation.
RESULTS: Thymic selection of hTCR T cells differed between the 2 major histocompatibility complex class II alleles, with normal CD4+ T-cell development observed solely under HLA-DR4 restriction. The chimeric hTCR maintained its citTNC22 specificity in vitro and ex vivo, without cross-reactivity to native TNC22 or other citrullinated autoantigens. hTCR-tg CD4+ T cells responded to antigen challenge in vivo and provided support to IgG class-switch and antigen-specific antibody production. Moreover, protein-immunised hTCR-tg mice developed arthritis after periarticular challenge with citTNC.
CONCLUSIONS: hTCR-tg mice expressing an RA patient-derived autoreactive TCR develop functional antigen-specific and HLA-restricted CD4+ T cells. The combination of humanised HLA-DR4 and TNC22 mice will be a valuable tool in the development of antigen-specific therapies translatable to human disease.