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

Megan L Burger,Margaux J Bennett,Astar Winoto,Kenneth K Leung

doi:10.7554/elife.03468

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.

Highlights

Maintenance of T cell self-tolerance is essential for the prevention of autoimmune diseases
By intracellular staining with an antibody that detects both mouse and human Bcl-2, we observed that Bcl-2 expression was significantly increased in Bcl-2 homology domain 3 (BH3) Tg thymocytes compared to wild-type controls (Figure 1B)
The transgene is expressed by the Cd4 promoter, increased Bcl-2 expression was detected in DN (CD4− CD8− double negative) thymocytes as early as CD25+ CD44− DN3 (Figure 1B)

Summary

Introduction

Maintenance of T cell self-tolerance is essential for the prevention of autoimmune diseases. During T cell development, autoreactive T cells bind selfpeptide presented on major histocompatibility complex (MHC) molecules with high affinity and receive strong T cell receptor (TCR) signals that trigger apoptosis and clonal deletion Some of these cells can differentiate down an alternative pathway to a harmless lineage, such as T regulatory cells (Treg), or CD8αα and invariant NK T cells (Stritesky et al, 2012). The importance of this process, termed negative selection, in establishing self-tolerance and preventing autoimmunity was best demonstrated in studies of mice deficient in the autoimmune regulator (Aire) gene. This has cast doubt on the relative importance of negative selection for maintaining immunological self-tolerance

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