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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Functional responsiveness of B6.Sle3.OT-II T cells. (A) B6.OT-II and B6....
Functional responsiveness of B6.Sle3.OT-II T cells. (A) B6.OT-II and B6.Sle3.OT-II splenocytes were cultured with various stimuli and assessed for proliferation. Stimulation index was cpmexperiment/cpmno-antigen. The cpmno-antigen values ranged from 2,000 to 5,000. Each dot represents an independent spleen sample. Horizontal bars indicate the respective group means. The data shown were reproduced in 2 additional studies (Supplemental Table 1 [supplemental material available online with this article; doi:10.1172/JCI23049DS1]). (B) B6.OT-II splenic T cells were transferred i.v. into 2-month-old B6 or B6.Sle3 mice on D0 and challenged with an immunogenic form of OVA on D1, as described in Methods. Seven days after transfer, the numbers of Tg T cells in the recipient spleens (left) and serum IgG anti-OVA levels (right) were assessed. Horizontal bars indicate group means. The displayed data were pooled from 2 independent studies using 5 mice per strain. (C) B6.OT-II and B6.Sle3.OT-II mice (n = 5 per group) were challenged with OVA323–339 in incomplete Freund’s adjuvant on D0; splenocytes were isolated on D5 and assessed for their proliferative response to OVA323–339. The vertical bars represent the SEM of triplicate cultures. Data shown are representative of 2 independent studies. Observed differences were not statistically significant. (D) B6.OT-II and B6.Sle3.OT-II mice (n = 5 mice per group) were challenged first with tolerogenic OVA on D0 and then with immunogenic OVA on D10 and examined as described in Methods. The vertical bars represent the SEM of triplicate cultures. In a second confirmatory study (data not shown), the fold difference in cpm between the 2 strain groups was 1.9 (P < 0.04, n = 4 each), at an OVA stimulation dose of 1,000 nM.