Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells
Jianmei W. Leavenworth, … , Xiaoyang Wang, Harvey Cantor
Jianmei W. Leavenworth, … , Xiaoyang Wang, Harvey Cantor
Published February 8, 2013
Citation Information: J Clin Invest. 2013;123(3):1382-1389. https://doi.org/10.1172/JCI66938.
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Research Article Inflammation

Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells

Abstract

Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60p216 and Qdm. We found that peptide-induced expansion of tetramer-binding CD8+ Tregs that recognize Qa-1–Hsp60p216 but not Qa-1–Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (TFH) and Th17 cells by CD8+ Tregs inhibited disease development. Infusion of in vitro–expanded CD8+ Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1–Hsp60p216–specific CD8+ Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60p216 peptide immunization. These results suggest that strategies designed to expand Qa-1–restricted (HLA-E–restricted), peptide-specific CD8+ Tregs represent a promising therapeutic approach to autoimmune disorders.

Authors

Jianmei W. Leavenworth, Xiaolei Tang, Hye-Jung Kim, Xiaoyang Wang, Harvey Cantor

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Figure 4

Transfer of in vitro IL-15C–expanded CD8+ Tregs inhibits CIA.

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Transfer of in vitro IL-15C–expanded CD8+ Tregs inhibits CIA. (A) CD12...
(A) CD122+CD44hiLy49+ or CD122+CD44hiLy49– CD8+ cells sorted from cCII-immunized B6 mice were incubated in 10 ng ml–1 IL-15C × 1 week. Purified CD25– CD4+ and B cells from arthritic donors were transferred with or without the indicated CD8+ cells (0.6 × 105) into Rag2–/–Prf1–/– mice followed by arthritis induction at day 0 and boost at days 21 and 35 (black arrows). Serum titers of anti-mouse CII IgG are shown. ***P < 0.001. (B) Arthritis scores are shown for 5–6 mice/group. Group (no CD8) vs. group (Ly49+ CD8), *P < 0.05. Data represent 3 independent experiments. (C) In vitro–expanded CD122+CD44hiLy49+ CD8+ cells (2 × 105) were transferred into B6 mice at days 0 and 18 (triangles). cCII immunization and boosting at days 0 and 21 (black arrows) and arthritis scores over 50 days are shown. (D) Numbers of TFH and IL-17–expressing CD4+ cells from inflamed joints in C are shown for 5–6 mice/group. (E) 0.75 mg/kg MTX was injected into B6 mice from day 21 to day 23 (arrows) after development of arthritis (average score of 4.5). In vitro IL-15C–expanded CD122+CD44hiLy49+ CD8+ cells (2.5 × 105) were transferred into mice at days 27, 30, and 38 (triangles). Arthritis scores are shown for 5–8 mice/group. Group (control) or group (MTX) versus group (CD8+ Treg + MTX) difference: *P < 0.05.