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Program Death-1 Suppresses Autoimmune Arthritis by Inhibiting Th17 Response

  • Lifen Yang
  • Guilin Qiao
  • Yassir Hassan
  • Zhenping Li
  • Xiaoqing Zhang
  • Huimin Kong
  • Weimin Zeng
  • Fei Yin
  • Jian Zhang
Original Article

Abstract

Program death-1 (PD-1) is a co-inhibitory receptor inducibly expressed on activated T cells. PD-1 has been reported to be associated with the development of several autoimmune diseases including rheumatoid arthritis, but the precise cellular and molecular mechanisms have not been fully elucidated. To study the role of PD-1 in the pathogenesis of rheumatoid arthritis and the possible underlying mechanisms, we performed collagen-induced arthritis (CIA) in C57BL/6 mice. Here, we show that PD-1 deficiency leads to the development of severe CIA in mice. When analyzing T cells from CIA mice ex vivo, we noticed aberrant antigen-specific Th17 responses in mice lacking PD-1. This is possibly due to deregulated activation of PKC-θ and Akt. In support of this notion, treating Pdcd1 −/− mice with an inhibitor of PI3-kinase that is upstream of PKC-θ and Akt significantly suppressed the disease severity. Therefore, our data indicate that PD-1 dampens antigen-specific Th17 response, thus inhibiting the disease.

Keywords

Program death-1 Collagen-induced arthritis Th17 PI3-kinase Akt 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (NNSF 81201371, to L. Yang), Young Researcher Culturing Plan from Xiangya Hospital, Young Teacher Exploring Plan from Central South University (to L. Yang) and NIH R01 AR049775 and AI090901 (to J. Zhang).

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

References

  1. Brand DD, Latham KA, Rosloniec EF (2007) Collagen-induced arthritis. Nat Protoc 2:1269–1275CrossRefPubMedGoogle Scholar
  2. Buttgereit F, Zhou H, Kalak R et al (2009) Transgenic disruption of glucocorticoid signaling in mature osteoblasts and osteocytes attenuates K/BxN mouse serum-induced arthritis in vivo. Arthritis Rheum 60:1998–2007CrossRefPubMedGoogle Scholar
  3. Chabaud M, Durand JM, Buchs N et al (1999) Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963–970CrossRefPubMedGoogle Scholar
  4. Hamel KM, Cao Y, Wang Y et al (2010) B7-H1 expression on non-B and non-T cells promotes distinct effects on T- and B-cell responses in autoimmune arthritis. Eur J Immunol 40:3117–3127CrossRefPubMedPubMedCentralGoogle Scholar
  5. Hu L, Zaloudek C, Mills GB et al (2000) In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 6:880–886PubMedGoogle Scholar
  6. Iliopoulos D, Kavousanaki M, Ioannou M et al (2011) The negative costimulatory molecule PD-1 modulates the balance between immunity and tolerance via miR-21. Eur J Immunol 41:1754–1763CrossRefPubMedGoogle Scholar
  7. Keir ME, Butte MJ, Freeman GJ et al (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704CrossRefPubMedGoogle Scholar
  8. Koch AE (2007) The pathogenesis of rheumatoid arthritis. Am J Orthop 36(7 suppl):5–8PubMedGoogle Scholar
  9. Koenders MI, Kolls JK, Oppers-Walgreen B et al (2005) Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced arthritis. Arthritis Rheum 52:3239–3247CrossRefPubMedGoogle Scholar
  10. Kondo Y, Iizuka M, Wakamatsu E et al (2012) Overexpression of T-bet gene regulates murine autoimmune arthritis. Arthritis Rheum 64:162–172CrossRefPubMedGoogle Scholar
  11. Kurebayashi Y, Nagai S, Ikejiri A et al (2012) PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating gfi1 expression and nuclear translocation of RORγ. Cell Rep 1:360–373CrossRefPubMedGoogle Scholar
  12. Li J, Wei B, Guo A et al (2013) Deficiency of β-arrestin1 ameliorates collagen-induced arthritis with impaired TH17 cell differentiation. Proc Natl Acad Sci USA 110:7395–7400CrossRefPubMedPubMedCentralGoogle Scholar
  13. Lin SC, Yen JH, Tsai JJ et al (2004) Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum 50:770–775CrossRefPubMedGoogle Scholar
  14. Lubberts E, Joosten LA, van de Loo FA et al (2002) Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction. Inflamm Res 51:102–104CrossRefPubMedGoogle Scholar
  15. Lubberts E, Koenders MI, Oppers-Walgreen B et al (2004) Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheum 50:650–659CrossRefPubMedGoogle Scholar
  16. Ma J, Ding Y, Fang X et al (2012) Protein kinase C-θ inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. J Immunol 188:5337–5347CrossRefPubMedPubMedCentralGoogle Scholar
  17. Miossec P, Kolls JK (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 11:763–776CrossRefPubMedGoogle Scholar
  18. Nakae S, Nambu A, Sudo K et al (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173–6177CrossRefPubMedGoogle Scholar
  19. Okazaki T, Honjo T (2006) The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27:195–201CrossRefPubMedGoogle Scholar
  20. Qiao G, Yang L, Li Z et al (2012) Program death-1 regulates peripheral T cell tolerance via an anergy-independent mechanism. Clin Immunol 143:128–133CrossRefPubMedPubMedCentralGoogle Scholar
  21. Skon CN, Lee JY, Anderson KG et al (2013) Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat Immunol 14:1285–1293CrossRefPubMedPubMedCentralGoogle Scholar
  22. Toyama S, Tamura N, Haruta K et al (2010) Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice. Arthritis Res Ther 12:R92CrossRefPubMedPubMedCentralGoogle Scholar
  23. Wang G, Hu P, Yang J et al (2011) The effects of PDL-Ig on collagen-induced arthritis. Rheumatol Int 31:513–519CrossRefPubMedGoogle Scholar
  24. Wehrens EJ, Prakken BJ, van Wijk F (2012) T cells out of control—impaired immune regulation in the inflamed joint. Nat Rev Rheumatol 9:34–42CrossRefGoogle Scholar
  25. Ying H, Yang L, Qiao G et al (2010) Cutting edge: CTLA-4–B7 interaction suppresses Th17 cell differentiation. J Immunol 185:1375–1378CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2016

Authors and Affiliations

  • Lifen Yang
    • 1
    • 2
  • Guilin Qiao
    • 2
  • Yassir Hassan
    • 2
  • Zhenping Li
    • 2
  • Xiaoqing Zhang
    • 1
  • Huimin Kong
    • 1
  • Weimin Zeng
    • 4
  • Fei Yin
    • 1
  • Jian Zhang
    • 2
    • 3
  1. 1.Department of Pediatrics, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  2. 2.Section of Nephrology, Department of MedicineThe Committees on Immunology and Molecular Medicine, The University of ChicagoChicagoUSA
  3. 3.Department of Microbial Infection and ImmunityThe Ohio State UniversityColumbusUSA
  4. 4.Department of Physiology, Xiangya Medical SchoolCentral South UniversityHunanPeople’s Republic of China

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