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Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance
Brian W. Busser, … , Jan Erikson, Terri M. Laufer
Brian W. Busser, … , Jan Erikson, Terri M. Laufer
Published November 1, 2003
Citation Information: J Clin Invest. 2003;112(9):1361-1371. https://doi.org/10.1172/JCI18310.
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Article Immunology

Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance

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Abstract

CD4+ helper T cells play a critical role in the production of the antinuclear autoantibodies that characterize systemic lupus erythematosus in mice and humans. A key issue is whether this help is derived from a diverse repertoire of autoreactive CD4+ T cells or from a select number of T cells of limited specificity. We used the chronic graft-versus-host disease model to define the diversity of the CD4+ T cell repertoire required to induce the autoantibody response. By transferring clonally restricted versus clonally diverse populations of MHC class II–reactive CD4+ T cells, we show that the loss of B cell tolerance to nuclear antigens has two distinct components with different CD4+ cell requirements. Activation of limited repertoires of CD4+ T cells was sufficient for the expansion of anergized anti–double-stranded DNA B cells and production of IgM autoantibodies. Unexpectedly, we found that CD4+ T cell diversity was necessary for CD4+ T cell trafficking into the follicle and for the generation of isotype-switched IgG autoantibodies. Importantly, combining two limited repertoires of T cells provides sufficient CD4+ T cell diversity to drive antinuclear Ab production. These data demonstrate that a diverse CD4+ T cell repertoire is required to generate a sustained effector B cell response capable of mediating systemic autoimmunity.

Authors

Brian W. Busser, Brigette S. Adair, Jan Erikson, Terri M. Laufer

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Figure 1

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Proliferation of I-Ab–reactive CD4+ T cells in B6 mice. B6 mice were inj...
Proliferation of I-Ab–reactive CD4+ T cells in B6 mice. B6 mice were injected (intravenously) with 5 × 106 CFSE-labeled CD4+ T cells. After 42 hours, animals were euthanized and spleen cells stained with anti-CD4 and analyzed by flow cytometry. Histograms show the division history of gated live splenic CFSE+ CD4+ T cells. Percentage of CD4+ T cells responding to B6 APCs is shown in the upper-left corner of the histogram. The y axis is at least 100 events for each histogram. Representative results from three independent experiments are shown.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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