T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity

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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, T_reg 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.

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Megan L Burger

University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Kenneth K Leung

University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Margaux J Bennett

University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Astar Winoto

University of California, Berkeley, Berkeley, United States

For correspondence
winoto@berkeley.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal related procedures were carried out according to protocols (#RO33) approved by the institutional animal care and use committee of the University of California at Berkeley.

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