BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice

Eliana Marino Moreno, Stacey N Walters, Jeanette E Villanueva, James L Richards, Charles R Mackay, Shane T Grey

    Research output: Contribution to journalArticleResearchpeer-review

    12 Citations (Scopus)

    Abstract

    Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.
    Original languageEnglish
    Pages (from-to)983 - 993
    Number of pages11
    JournalEuropean Journal of Immunology
    Volume44
    Issue number4
    DOIs
    Publication statusPublished - 2014

    Cite this

    Marino Moreno, Eliana ; Walters, Stacey N ; Villanueva, Jeanette E ; Richards, James L ; Mackay, Charles R ; Grey, Shane T. / BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice. In: European Journal of Immunology. 2014 ; Vol. 44, No. 4. pp. 983 - 993.
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    abstract = "Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.",
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    BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice. / Marino Moreno, Eliana; Walters, Stacey N; Villanueva, Jeanette E; Richards, James L; Mackay, Charles R; Grey, Shane T.

    In: European Journal of Immunology, Vol. 44, No. 4, 2014, p. 983 - 993.

    Research output: Contribution to journalArticleResearchpeer-review

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    AU - Walters, Stacey N

    AU - Villanueva, Jeanette E

    AU - Richards, James L

    AU - Mackay, Charles R

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