Effects of Altered IFNAR Expression on CD4\+CD25\+ Treg Cell Dysfunction in Patients with Systemic Lupus Erythematosus

HE Yan, PENG Yun, TAN Chun-yu. et al

Abstract

To explore the role of type Ⅰ interferon (IFNα) on the function of CD4\+CD25\+ regulatory T (Treg) cells in patients with systemic lupus erythematosus (SLE). Methods Twenty patients with newly-onset active SLE and 20 healthy controls were recruited in this study. The expressions of type Ⅰ interferon α receptor (IFNAR) on Treg cells were analyzed using flow cytometry. CD4\+CD25\+ Treg cells were purified by magnetic-activated cell sorter (MACS). The function of these cells was assessed \in vitro with or without IFNα (500 U/mL). The effect of exogenous IFNα on the apoptosis of Treg cells and the expression level of FOXP3, CTLA-4, and pAKT in Treg cells were analyzed using flow cytometry. Results The expression levels of IFNAR1 on CD4\+CD25\+ Treg cells were significantly higher in the SLE patients than in the healthy controls (\P=0.000 6). There was a positive correlation between the expression levels of IFNAR on Treg cells and the SLEDAI scores in the SLE patients. Exogenous IFNα impaired the suppressive capacity of Treg cells in the SLE patients. However, neither the apoptosis of Treg cells nor the expression levels of FOXP3 and CTLA-4 on Treg cells were influenced by IFNα stimulation. IFNα enhanced AKT phosphorylation in Treg cells in the SLE patients. Conclusion Altered IFNAR expression may contribute to Treg cell dysfunction in SLE patients through enhancing AKT phosphorylation in Treg cells.

 

Keywords: Regulatory T cellsInterferon, Systemic lupus erythematosusImmune tolerance

 

Full Text:

PDF


References


Scheinecker С, Bonelli М, Smolen JS. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. J Autoimmun,2010;35(3):269-275.

Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity, 2006;25(3):383-392.

Vallin H, Blomberg S, Aim GV, et al. Patients with systemic lupus erythematosus ( SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells. Clin Exp Immunol. 1999 ; 115(1):196-202.

Weckerle CE, Franek BS, Kelly JA, et al. Network analysis of associations between serum interferon-alpha activity, autoantibodies, and clinical features in systemic lupus erythematosus. Arthritis Rheum .2011; 63( 4); 1044-1053.

Crow MK. Advances in understanding the role of type I interferons in systemic lupus erythematosus. Curr Opin Rheumatol,2014;26(5) :467-474.

Yan B, Ye S, Chen G, et al. Dysfunctional CD4+ , CD25 + regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen- presenting cells. Arthritis Rheum,2008;58(3):801 -812.

Blanco P, Palucka AK, Gill M. et al. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science,2001 ;294(5546) : 1540-1543.

Srivastava S, Koch MA, Pepper M. et al. Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. J Exp Med.2014; 211(5):961-974.

Golding A, Rosen A, Petri M, et al. Interferon-alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses. Immunology,2010; 131(1); 107-117.

Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol,2014; 14(1) ;36-49.

Santiago-Raber ML. Baccala R, Haraldsson KM. et al, Type- I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med.2003; 197(6);777-788.

Agrawal H, Jacob N. Carreras E, et al. Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease. J Immunol.2009; 183(9) :6021-6029.

Kirou KA. Gkrouzman E. Anti-interferon alpha treatment in SLE. Clin Immunol,2013; 148(3);303-312.

Wing K. Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol, 2010;11(1) :7-13.

Weichhart T, Saemann MD. The Р13К/Akt/mTOR pathway in innate immune cells; emerging therapeutic applications. Ann Rheum Dis,2008;67(Suppl 3);iii70-iii74.

Soond DR. Slack ECM, Garden OA, et al. Does the PI3K pathway promote or antagonize regulatory T cell development and function. Front Immunol, 2012; 3: 244. doi: 10. 3389/ fimmu. 2012. 00244.

Abu-Eid R, Samara RN, Ozbun L. et al. Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway. Cancer Immunol Res,2014 ;2( 11): 1080-1089.

Crellin NK, Garcia RV, Levings MK. Altered activation of АКТ is required for the suppressive function of human CD4 CD25+ T regulatory cells. Blood,2007; 109(5) ;2014-2022.


Refbacks

  • There are currently no refbacks.