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

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.DOI: http://dx.doi.org/10.7554/eLife.03468.001

Nur77 Regulates Nondeletional Mechanisms of Tolerance in T Cells

“…Recent studies support an inverse relationship between clonal deletion and lineage diversion. When clonal deletion was impaired by Bim deficiency, abrogation of CD28/B7 costimulation, or Bcl-2 transgenic overexpression, increases in nonconventional fates, such as Tregs, anergic phenotype CD4 + T cells, and postselection double-negative thymocytes were found (27)(28)(29). Furthermore, attenuation of TCR signaling potential through modulation of the TCRz chain impaired clonal deletion but resulted in increased Treg development (30).…”

“…In an Ag-specific model of arthritis, anergic CD4 + T cells were marked by high expression of FR4 and CD73 (7). Like Tregs, FR4 hi CD73 hi CD4 + T cells experience stronger TCR signaling than conventional T cells (29) and were increased in Bim-deficient and Bcl-2-transgenic mice (27,29). Studies have not yet examined whether this subset can be found in the thymus, and it is unknown whether these cells can arise during thymic selection.…”

The Inflammatory Signal Adaptor RIPK3: Functions Beyond Necroptosis

“…Genetic studies in C. elegans laid the foundation for discovery of numerous apopotosis genes and the signaling network that regulates it. These discoveries unveiled the important physiological roles of apoptosis in embryonic development (Ellis and Horvitz, 1986), immune homeostasis (Burger et al, 2014), and cancer (Hockenbery et al, 1990; Tsujimoto et al, 1985). In contrast, since necrotic cell death is often observed when cells are exposed to excessive physical or chemical stresses, it was considered to be an un-programmed and accidental cell death.…”

B cell lymphoma 2 (Bcl-2) residues essential for Bcl-2's apoptosis-inducing interaction with Nur77/Nor-1 orphan steroid receptors

“…This Bcl-2 mutant exhibits increased anti-apoptotic activity and rescues more autoreactive T cells when compared to transgenic wild-type Bcl-2. Most strikingly, unlike wild-type Bcl-2 transgenic mice, these mice exhibited accelerated death from multi-organ autoimmunity (46).…”

“…This may convert Bcl-2's normal antiapoptotic activity into a killer, pro-apoptotic protein, possibly through saturation binding of Bcl-x (44,45). The importance of the Bcl-2 BH3 domain was demonstrated in transgenic mice engineered to express a Bcl-2 protein with its BH3 domain mutated in T cells (46). This Bcl-2 mutant exhibits increased anti-apoptotic activity and rescues more autoreactive T cells when compared to transgenic wild-type Bcl-2.…”