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

Abstract：

: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.

journal_name

Mol Immunol

journal_title

Molecular immunology

authors

Orlando L,Accomasso L,Circosta P,Turinetto V,Lantelme E,Porcedda P,Minieri V,Pautasso M,Willemsen RA,Cignetti A,Giachino C

doi

10.1016/j.molimm.2011.02.015

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

1369-76

issue

12-13

eissn

0161-5890

issn

1872-9142

pii

S0161-5890(11)00105-2

journal_volume

48

pub_type

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