Regulatory T cells are less sensitive to glucocorticoid hormone induced apoptosis than CD4 + T cells
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Regulatory T cells are less sensitive to glucocorticoid hormone induced apoptosis than CD4+ T cells Lilla Prenek1 · Tímea Litvai1 · Noémi Balázs1 · Réka Kugyelka1 · Ferenc Boldizsár1 · József Najbauer1 · Péter Németh1 · Timea Berki1
© The Author(s) 2020
Abstract Earlier we have reported that thymic regulatory T cells (Treg) are resistant to in vivo glucocorticoid hormone (GC)-induced apoptosis, while the most GC-sensitive DP thymocytes died through the activation of mitochondrial apoptotic pathway. Here we analyzed the apoptosis-inducing effect of high dose (10–6 M) in vitro dexamethasone (DX) treatment in mouse thymicand splenic Tregs and CD4+ T cells. Activation of both extrinsic and intrinsic apoptotic pathways started after 2 h of DX treatment in CD4 SP thymocytes and was 3 × higher than in C D4+ splenocytes, while in Treg cells, weak activation of the extrinsic apoptotic pathway started only after 3 h. We also investigated the expression of 21 apoptosis-related molecules using a protein array and found higher level of both pro-and anti-apoptotic molecules in Tregs compared to CD4+ T cells. 4 h in vitro DX treatment induced upregulation of most apoptosis-related molecules both in Tregs and C D4+ T cells, except for + 2+ the decrease of Bcl-2 expression in C D4 T cells. We found high basal cytosolic C a levels in untreated Treg cells, which further increased after DX treatment, while the specific TCR-induced Ca2+ signal was lower in Tregs than in CD4+ T cells. Our results suggest that in the background of the relative apoptosis resistance of Treg cells to GCs might be their high basal cytosolic Ca2+ level and upregulated Bcl-2 expression. In contrast, downregulation of Bcl-2 expression in CD4+ T cells can explain their higher, DX-induced apoptosis sensitivity. Keywords Glucocorticoid hormone · Dexamethasone · Thymocytes · Splenocytes · CD4+ Th cells · pTreg · tTreg · Apoptosis · Caspase · Ca2+ signaling Abbreviations BSA Bovine serum albumin Ctrl Control DMSO Dimethyl sulfoxide DP Double positive DX Dexamethasone GC Glucocorticoid HIF-1α Hypoxia-inducible factor 1-alpha HO-1 Heme oxygenase 1 HSP60 Heat shock protein 60 kDa iTreg Induced regulatory T cell MCL-1 Induced myeloid leukemia cell differentiation protein Mcl-1 NaN3 Sodium azide * Timea Berki [email protected] 1
Department of Immunology and Biotechnology, Clinical Center, Medical School, University of Pécs, Szigeti út 12, Pécs 7624, Hungary
PBS Phosphate buffered saline pTreg Peripheral regulatory T cell RT Room temperature SMAC Second mitochondria-derived activator of caspase SP Single positive TCR T cell receptor Th Helper T cell TNFRI Tumor necrosis factor receptor I TRARIL R2 Tumor necrosis factor receptor superfamily member 10B tTreg Thymic regulatory T cell XIAP X-linked inhibitor of apoptosis
Introduction Glucocorticoid hormones (GCs) regulate essential physiologic functions, control metabolism, growth, differentiation, and apoptosis of numerous cell types [1–3]. GCs also
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