T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity.
Elife
; 32014 Sep 02.
Article
in En
| MEDLINE
| ID: mdl-25182415
ABSTRACT
T cell self-tolerance is thought to involve peripheral tolerance and negative selection, involving apoptosis of autoreactive thymocytes. However, evidence supporting an essential role for negative selection is limited. Loss of Bim, a Bcl-2 BH3-only protein essential for thymocyte apoptosis, rarely results in autoimmunity on the C57BL/6 background. Mice with T cell-specific over-expression of Bcl-2, that blocks multiple BH3-only proteins, are also largely normal. The nuclear receptor Nur77, also implicated in negative selection, might function redundantly to promote apoptosis by associating with Bcl-2 and exposing its potentially pro-apoptotic BH3 domain. Here, we report that T cell-specific expression of a Bcl2 BH3 mutant transgene results in enhanced rescue of thymocytes from negative selection. Concomitantly, Treg development is increased. However, aged BH3 mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Autoimmunity
/
Apoptosis
/
Self Tolerance
Type of study:
Etiology_studies
Limits:
Animals
/
Humans
Language:
En
Year:
2014
Type:
Article