Review Emerging pathways of non-genomic glucocorticoid (GC) signalling in T cells Ferenc Boldizsar n , Gergely Talaber, Mariann Szabo, Domokos Bartis, Laszlo Palinkas, Peter Nemeth, Timea Berki Department of Immunology and Biotechnology, Faculty of Medicine, University of Pecs, 7624 Pecs, Szigeti ut. 12., Hungary article info Article history: Received 19 August 2009 Received in revised form 9 October 2009 Accepted 13 October 2009 Keywords: Glucocorticoid hormone Mitochondrion Non-genomic effects T cell ZAP-70 abstract In the last decade new glucocorticoid (GC)-signalling mechanisms have emerged. The evolving field of non-genomic GC actions was precipitated from two major directions: (i) some rapid/acute clinical GC applications could not be explained based on the relatively slowly appearing genomic GC action and (ii) accumulating evidence came to light about the discrepancy in the apoptosis sensitivity and GR expression of thymocytes and other lymphoid cell types. Herein, we attempt to sample the latest information in the field of non-genomic GC signalling in T cells, and correlate it with results from our laboratory. We discuss some aspects of the regulation of thymocyte apoptosis by GCs, paying special interest to the potential role(s) of mitochondrial GR signalling. The interplay between the T cell receptor (TcR) and glucocorticoid receptor (GR) signalling pathways is described in more detail, focusing on ZAP- 70, which is a novel target of rapid GC action. & 2009 Elsevier GmbH. All rights reserved. Contents Genomic- and non-genomic GC effects ................................................................................ 521 Cross-talk between the GR and TcR signalling proteins .................................................................... 522 GC regulation of T cell development ................................................................................... 523 Mitochondrial GR.................................................................................................. 523 Concluding remarks ................................................................................................ 524 References ....................................................................................................... 525 Genomic- and non-genomic GC effects Classically, GC hormones exert their effects through the nuclear translocation of the ligand-bound GR from the cytoplasm, which then acts as a transcription factor, and binds to glucocorti- coid responsive elements (GRE) in the promoter region of several target genes (Drouin et al. 1992; Berg 1989)(Fig. 1). The GR is a member of the steroid receptor superfamily, comprised of three functional domains: hormone-, DNA-binding- and a less conserved N-terminal domain (Evans 1988). The unliganded (inactive) GR forms a multi-molecular complex with heat shock proteins and immunophilins in the cytoplasm (Smith and Toft 1993). Upon ligand binding the GR dissociates from its chaperones reaching the active conformation by forming homodimers (Drouin et al. 1992). The number of genes regulated directly by the GR is estimated between 10 and 100 per cell (Hayashi et al. 2004). Thus, GCs exert a great range of effects on various tissues and cell types (Munck et al. 1984). Moreover, glucocorticoid hormone (GC) derivatives are widely used in anti-inflammatory and immuno- suppressive therapy due to their robust anti-inflammatory effects (Buttgereit et al. 2005). Non-genomic GC effects, on the other hand, are not mediated by such transcriptional activity, but through alternative pathways (Fig. 1). Buttgereit and colleagues have proposed 3 alternative GC mechanisms: (i) signalling through a (putative) membrane GR (mGR), (ii) direct membrane effect of the GCs and (iii) interaction of the GR with other signalling proteins in the cytoplasm (Buttgereit and Scheffold 2002)(Fig. 1). A fourth alternative GC signalling pathway has been established lately based on the mitochondrial GR translocation described in a number of cell types (Sionov et al. 2006a; Sionov et al. 2006b; Psarra et al. 2005; Du et al. 2009; Talaber et al. 2009)(Fig. 1). Membrane-bound GR (Fig. 1) was found in rodent and human lymphoid cell lines as well as in amphibian brain (Gametchu ARTICLE IN PRESS Contents lists available at ScienceDirect journal homepage: www.elsevier.de/imbio Immunobiology 0171-2985/$ - see front matter & 2009 Elsevier GmbH. All rights reserved. doi:10.1016/j.imbio.2009.10.003 Abbreviations: chronic lymphocytic leukaemia, CLL; glucocorticoid hormone, GC; glucocorticoid hormone receptor, GR; Tcell receptor, TcR; double positive, DP; dexamethasone, DX; green fluorescent protein, GFP n Corresponding author. Tel.: +36 72 536 288; fax: +36 72 536 289. E-mail address: fboldizsar@hotmail.com (F. Boldizsar). Immunobiology 215 (2010) 521–526