Publikationsdatum:
2011-04-09
Beschreibung:
Generation of a diverse and self-tolerant T-cell repertoire requires appropriate interpretation of T-cell antigen receptor (TCR) signals by CD4(+ ) CD8(+) double-positive thymocytes. Thymocyte cell fate is dictated by the nature of TCR-major-histocompatibility-complex (MHC)-peptide interactions, with signals of higher strength leading to death (negative selection) and signals of intermediate strength leading to differentiation (positive selection). Molecules that regulate T-cell development by modulating TCR signal strength have been described but components that specifically define the boundaries between positive and negative selection remain unknown. Here we show in mice that repression of TCR-induced death pathways is critical for proper interpretation of positive selecting signals in vivo, and identify schnurri-2 (Shn2; also known as Hivep2) as a crucial death dampener. Our results indicate that Shn2(-/-) double-positive thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T-cell development. Shn2(-/-) double-positive thymocytes are more sensitive to TCR-induced death in vitro and die in response to positive selection interactions in vivo. However, Shn2-deficient thymocytes can be positively selected when TCR-induced death is genetically ablated. Shn2 levels increase after TCR stimulation, indicating that integration of multiple TCR-MHC-peptide interactions may fine-tune the death threshold. Mechanistically, Shn2 functions downstream of TCR proximal signalling compenents to dampen Bax activation and the mitochondrial death pathway. Our findings uncover a critical regulator of T-cell development that controls the balance between death and differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077958/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Staton, Tracy L -- Lazarevic, Vanja -- Jones, Dallas C -- Lanser, Amanda J -- Takagi, Tsuyoshi -- Ishii, Shunsuke -- Glimcher, Laurie H -- AI29673/AI/NIAID NIH HHS/ -- K99AR055668/AR/NIAMS NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- R01 AI029673/AI/NIAID NIH HHS/ -- R01 AI029673-22/AI/NIAID NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Apr 7;472(7341):105-9. doi: 10.1038/nature09848.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21475200" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Animals
;
Apoptosis Regulatory Proteins/deficiency/genetics
;
Cell Death
;
Cell Differentiation
;
DNA-Binding Proteins/deficiency/genetics/*metabolism
;
Membrane Proteins/deficiency/genetics
;
Mice
;
Mice, Inbred BALB C
;
Mitochondria/metabolism/pathology
;
Proto-Oncogene Proteins/deficiency/genetics
;
Receptors, Antigen, T-Cell/immunology/metabolism
;
Signal Transduction
;
T-Lymphocytes/*cytology/immunology/metabolism
;
Thymus Gland/cytology/immunology
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
Permalink