Cell Survival Failure in Effector T Cells From Patients With Systemic Lupus Erythematosus Following Insufficient Up-Regulation of Cold-Shock Y-Box Binding Protein 1
Open Access
- 1 October 2020
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatology
- Vol. 72 (10), 1721-1733
- https://doi.org/10.1002/art.41382
Abstract
Objective The importance of cold-shock Y-box binding protein 1 (YB-1) for cell homeostasis is well-documented based on prior observations of its association with certain cancer entities. This study was undertaken to explore the role of YB-1 in T cell homeostasis and survival and the potential contribution of YB-1 to the pathogenesis of systemic lupus erythematosus (SLE). Methods In the peripheral blood from 25 SLE patients and 25 healthy donors, the expression of YB-1 and frequency of T cell apoptosis was analyzed by quantitative polymerase chain reaction (qPCR) and fluorescence-activated cell sorting of CD4+ T cells ex vivo and also analyzed in T cells in vitro after 6 days of stimulation with anti-CD3-coupled or anti-CD3/anti-CD28-coupled microspheres. YB-1 was overexpressed using lentiviral transduction with wild-type green fluorescent protein (wtGFP) YB-1, and knockdown of YB-1 was achieved using specific short hairpin RNA (shRNA) (3-fold reduction;P< 0.0001). Results YB-1 expression was significantly lower in apoptosis-prone T cells and in activated T cells from SLE patients compared to YB-1 expression in nonapoptotic T cells and activated T cells from healthy donors (P= 0.001). Knockdown of YB-1 in T cells consequently led to expression of proapoptotic molecules and caspase 3 activation (1.6-fold), and subsequently, to apoptosis. Furthermore, YB-1 promoted survival pathways involving enhanced protein expression of the kinase Akt (2-fold) and Bcl-2 (3-fold), even when Fas/CD95 was triggered. YB-1-mediated T cell survival was reversed by Akt and phosphatidylinositol 3-kinase (PI3K) inactivation. In SLE patients, rescue of YB-1 expression strongly promoted survival of T cells and even prevented cell death in T cells that were extremely apoptosis-prone. Conclusion Our data show that failure of YB-1 up-regulation in T cells from SLE patients led to enhanced apoptosis. These findings imply that YB-1 plays a crucial role in the disturbed homeostasis of activated T cells leading to hematopoietic alterations in SLE. These insights may help facilitate the development of new treatment strategies for SLE.Keywords
This publication has 52 references indexed in Scilit:
- Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus ErythematosusPublished by The American Association of Immunologists ,2013
- Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family MoleculesFrontiers in Immunology, 2013
- Protective Roles of Natural IgM AntibodiesFrontiers in Immunology, 2012
- PUMA, a potent killer with or without p53Oncogene, 2008
- Bcl-XL Inhibits Membrane Permeabilization by Competing with BaxPLoS Biology, 2008
- CD152 (CTLA-4) Determines the Unequal Resistance of Th1 and Th2 Cells against Activation-induced Cell Death by a Mechanism Requiring PI3 Kinase FunctionThe Journal of Experimental Medicine, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Direct interaction of p53 with the Y-box binding protein, YB-1: a mechanism for regulation of human gene expressionOncogene, 2000
- High levels of bcl‐2 protein in circulating t lymphocytes, but not b lymphocytes, of patients with systemic lupus erythematosusArthritis & Rheumatism, 1994
- Derivation of the sledai. A disease activity index for lupus patientsArthritis & Rheumatism, 1992