T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells
JianKun Zhu, … , Edward K. Wakeland, Chandra Mohan
JianKun Zhu, … , Edward K. Wakeland, Chandra Mohan
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1869-1878. https://doi.org/10.1172/JCI23049.
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Research Article Immunology

T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells

Abstract

Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-Ab, and CD40, and their elevated production of various cytokines, including IL-12 and IL-1β, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.

Authors

JianKun Zhu, XueBin Liu, Chun Xie, Mei Yan, Ying Yu, Eric S. Sobel, Edward K. Wakeland, Chandra Mohan

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Figure 6

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B6.Sle3 DCs are superior APCs for T cell stimulation. (A–D) DCs cultured...
B6.Sle3 DCs are superior APCs for T cell stimulation. (A–D) DCs cultured from 2-month-old B6 (A and C) or B6.Sle3 (B and D) BM, using GM-CSF plus IL-4 for 7 days, were pulsed with OVA323–339, and cocultured with CFSE-labeled, OVA-specific B6.OT-II TCR Tg T cells (A and B) or non-Tg T cells (C and D), and the fraction of T cells that had undergone cell division was assessed by flow cytometry. The histograms pertain to coculture studies that were performed with 10,000 OVA-pulsed DCs, and examined by flow cytometry 96 hours after stimulation. (E) Similar results were obtained using OVA-pulsed CD11c bead–purified splenic DCs from B6 and B6.Sle3 mice cocultured with B6.OT-II or B6.Sle3.OT-II T cells for 96 hours; however, any apparent differences noted failed to attain statistical significance. The data depicted in E are representative of 3 independent experiments. In addition, OVA-specific B6.OT-II TCR Tg T cells were cocultured with varying numbers of unpulsed B6 (white dots) or B6.Sle3 (black dots) BM-cultured DCs and 1,000 nM OVA323–339 (F), or with 50,000 unpulsed BM-derived DCs and varying doses of OVA323–339 (G). In both experiments, proliferation was assessed 96 hours after culture, by assaying of 3H-thymidine incorporation. The data portrayed in F and G are representative of 3 independent experiments; an additional experiment is displayed in H, where the proliferation of B6.OT-II and B6.Sle3.OT-II TCR Tg T cells in response to varying numbers of OVA-pulsed B6 or B6.Sle3 splenic CD11c bead–purified DCs was assessed. Shown P values were computed by comparison of the B6.Sle3 values with the B6 control values, using the Student’s t test.