| First Author | Burger ML | Year | 2014 |
| Journal | Elife | Volume | 3 |
| PubMed ID | 25182415 | Mgi Jnum | J:217939 |
| Mgi Id | MGI:5616262 | Doi | 10.7554/eLife.03468 |
| Citation | Burger ML, et al. (2014) T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity. Elife 3 |
| abstractText | 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. |
