TCR transfer induces TCR-mediated tonic inhibition of RAG genes in human T cells.

Autor: Orlando L; Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy. luca.orlando@unito.it, Accomasso L, Circosta P, Turinetto V, Lantelme E, Porcedda P, Minieri V, Pautasso M, Willemsen RA, Cignetti A, Giachino C
Jazyk: angličtina
Zdroj: Molecular immunology [Mol Immunol] 2011 Jul; Vol. 48 (12-13), pp. 1369-76. Date of Electronic Publication: 2011 Apr 08.
DOI: 10.1016/j.molimm.2011.02.015
Abstrakt: Induction of the TCR signaling pathway terminates the expression of RAG genes, and a link between this pathway and their transcriptional control is evident from the recent demonstration of their re-expression if the TCR is subsequently lost or down-regulated. Since unstimulated T cells display a steady-state level of "tonic" TCR signaling, i.e. in the absence of any antigenic stimulus, it was uncertain whether this control was exerted through ligand-dependent or ligand-independent TCR signaling. Here we demonstrate for the first time that exogenous TCR α and β chains transferred into the human immature RAG(+) T cell line Sup-T1 by lentiviral transduction inhibit RAG expression through tonic signaling, and that this inhibition could itself be reverted by pharmacological tonic pathway inhibitors. We also suggest that mature T cells already expressing an endogenous TCR on their surface maintain some levels of plasticity at the RAG locus when their basal TCR signaling is interfered with. Lastly, we show that the TCR constructs employed in TCR gene therapy do not possess the same basal signaling transduction capability, a feature that may have therapeutic implications.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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