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 4

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Cytokine secretion profiles of B6.Sle3 DCs and macrophages. (A and B) CD...
Cytokine secretion profiles of B6.Sle3 DCs and macrophages. (A and B) CD11c magnetic bead–purified splenic DCs from 2- to 3-month-old B6 and B6.Sle3 mice (n = 4 per group; A), as well as CD11c magnetic bead–purified DCs cultured from B6 or B6.Sle3 BM (using GM-CSF alone, for 7 days; n = 8–9 mice per group; B), were incubated for 24 hours, with or without 10 ng/ml LPS. Depicted are the IL-12 (p70), IL-6, and IL-1β levels in 24-hour culture supernatant. Each dot represents data derived from splenic or BM DCs of an individual mouse; where the positions of the dots overlap, this has been represented using single dots only, for clarity. Similar findings were noted in a second confirmatory study (Supplemental Figure 1A). (C–E) In addition, 24-hour IL-12, IL-6, and TNF-α secretion by B6- or B6.Sle3-derived BM-cultured macrophages in response to LPS was assessed by ELISA. Each dot represents data derived from the BM macrophages of an individual mouse. The horizontal bars represent group means. The data shown were reproduced in 2–3 additional experiments (Supplemental Figure 1B). The depicted P values in A–E were computed by comparison of the B6.Sle3 values with the B6 control values, using the Student’s t test.