Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up-regulating regulatory T cells.

Abstract

Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-γ expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORγt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy.

• Authors: Xia Liu, Baoju Ji, Mengyi Sun, Weijiang Wu, Lili Huang, Aihua Sun, Yangyong Zong, Sheng Xia, Liyun Shi, Hui Qian, Wenrong Xu, Qixiang Shao
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 181 Issue 1 Pg. 87-99 (Jul 2015) ISSN: 1365-2249 [Electronic] England
• PMID: 25809415 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 British Society for Immunology.

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• IL10 protein, mouse
• Il2ra protein, mouse
• Interleukin-17
• Interleukin-2
• Interleukin-2 Receptor alpha Subunit
• Nuclear Receptor Subfamily 1, Group F, Member 3
• Recombinant Fusion Proteins
• Interleukin-10
• Interferon-gamma

Topics

• Animals
• Arthritis, Experimental (drug therapy)
• Arthritis, Rheumatoid (drug therapy)
• Cell Differentiation (drug effects, immunology)
• Cell Proliferation (drug effects)
• Forkhead Transcription Factors (genetics, pharmacology)
• Interferon-gamma (biosynthesis)
• Interleukin-10 (biosynthesis)
• Interleukin-17 (biosynthesis)
• Interleukin-2 (biosynthesis)
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Lymphocyte Activation (drug effects, immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Nuclear Receptor Subfamily 1, Group F, Member 3 (metabolism)
• Recombinant Fusion Proteins (genetics, pharmacology)
• T-Lymphocytes, Regulatory (cytology, immunology)
• Th17 Cells (cytology, immunology)
• Up-Regulation