The BH3-Only Proteins Bim and Puma Cooperate to Impose Deletional Tolerance of Organ-Specific Antigens

Gray, Daniel H.D.; Kupresanin, Fiona; Berzins, Stuart P.; Herold, Marco J.; O’Reilly, Lorraine A.; Bouillet, Philippe; Strasser, Andreas

doi:10.1016/j.immuni.2012.05.030

Cited by 64 publications

(86 citation statements)

References 48 publications

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“…Through interactions with pro-and antiapoptotic Bcl-2 family members at mitochondria, Bim promotes release of cytochrome c and subsequent caspase activation. Unlike the critical role of Bim in TRA-mediated clonal deletion (15,16), Bim is not required for deletion in the HY cd4 model or other UbA-driven models (12,15,17). However, we found that Bim was essential for caspase-3 activation in thymocytes, suggesting that clonal deletion in HY cd4 Bim 2/2 mice was mediated by a caspase-independent cell death mechanism.…”

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confidence: 64%

“…In support of this, phosphorylation and subcellular localization of Nur77 have been shown to be different between stimulated DP thymocytes and mature CD8 + T cells (48). Likewise, in contrast to its lesser impact on UbA-mediated clonal deletion, Bim deficiency is known to block TRA-mediated deletion of CD8SP thymocytes (15,16). Given these context-dependent differences in the mechanism of clonal deletion, it would be of interest to assess the role of Nur77 in TRA-mediated deletion of CD8SP thymocytes as well.…”

Section: Discussionmentioning

confidence: 92%

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Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen

Baldwin

2015

The Journal of Immunology

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Negative selection, primarily mediated through clonal deletion of self-reactive thymocytes, is critical for establishing self-tolerance and preventing autoimmunity. Recent studies suggest that the molecular mechanisms of negative selection differ depending on the thymic compartment and developmental stage at which thymocytes are deleted. Using the physiological HYcd4 TCR transgenic model of negative selection against ubiquitous self-antigen, we previously found that one of the principal mediators implicated in clonal deletion, Bim, is required for caspase-3 activation but is ultimately dispensable for negative selection. On the basis of these data, we hypothesized that Nur77, another molecule thought to be a key mediator of clonal deletion, could be responsible for Bim-independent deletion. Despite comparable Nur77 induction in thymocytes during negative selection, Bim deficiency resulted in an accumulation of high-affinity–signaled thymocytes as well as impairment in caspase-mediated and caspase-independent cell death. Although these data suggested that Bim may be required for Nur77-mediated cell death, we found that transgenic Nur77 expression was sufficient to induce apoptosis independently of Bim. However, transgenic Nur77-induced apoptosis was significantly inhibited in the context of TCR signaling, suggesting that endogenous Nur77 could be similarly regulated during negative selection. Although Nur77 deficiency alone did not alter positive or negative selection, combined deficiency in Bim and Nur77 impaired clonal deletion efficiency and significantly increased positive selection efficiency. Collectively, these data shed light on the different roles for Bim and Nur77 during ubiquitous Ag-mediated clonal deletion and highlight potential differences from their reported roles in tissue-restricted Ag-mediated clonal deletion.

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contrasting

confidence: 64%

Section: Discussionmentioning

confidence: 92%

Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen

Baldwin

2015

The Journal of Immunology

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“…However, it is interesting to note that absence of Bim or overexpression of Bcl2/Bcl-Xl does not phenocopy the severe autoimmune pathology that occurs when negative selection is abrogated from loss of Aire expression (20). In fact, recent evidence suggests that additional loss of NOXA and PUMA is a requirement for autoimmune manifestation in Bimdeficient thymocytes (21), implying redundancy between BH3-only proteins during negative selection. We see little detectable expression of NOXA and PUMA in DP2 thymocytes in our system.…”

Section: Applying Apoptotic Stress To Thymocytes Preferentially Perturbsmentioning

confidence: 99%

Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

Sinclair

Bains

Yates

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

143

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It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable ∼75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis. CD4 T cells | CD8 T cellsD evelopment of CD4 and CD8 lineage cells from common thymic precursors is one of the most fundamental developmental processes in the adaptive immune system. The predominance of CD4 over CD8 T-cell populations in the periphery has been apparent since helper and cytotoxic T cells were first delineated more than 30 y ago (1), but the cause of this signature bias has remained obscure. A key contribution arises from the ratio in which CD4 and CD8 lineage T cells are generated by the thymus. Single-positive (SP) thymocytes exist in the thymus at ∼4:1, a ratio that is highly conserved across mouse strains and other species, suggesting that the developmental mechanisms involved are fundamental to the processes that give rise to mature T cells in the thymus. During thymocyte development, T-cell antigen receptor (TCR) genes undergo somatic rearrangements to generate a broad repertoire of TCR structures. Negative and positive selection of thymocytes results in the deletion of autoreactive thymocytes and ensures that class I and class II MHC reactivity is correlated with CD8 and CD4 lineage specification. The molecular mechanisms underpinning these processes are increasingly well understood. Although survival of thymocytes is regulated by expression of Bcl2 family members, up-regulation of the BH3-only family member Bim has been specifically implicated as a key event in negative selection of thymocytes (2). During positive selection, class II recognition is thought to induce strong persistent signaling that results in a cascade of transcriptional regulation by factors such as GATA3 and T-helper-inducing POZ/Krüppel-like factor, which results in fixation of cells to the CD4 lineage (3, 4). In contrast, weaker or transient signaling by class I MHC results in the cytokine-dependent induction of a Runx3-mediated transcriptional program that induces CD8 lineage commitment (5-8).Despit...

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“…Indeed, transcriptional upregulation of Noxa has been observed following the activation of both B-and T-cell antigen receptors and a co-operative role in T-cell receptor (TCR) stimulationinduced apoptosis has been demonstrated alongside Bim and Puma. 26,27,30,56 Furthermore, Noxa appears to sensitize lymphocytes with low-affinity antigen receptors toward cell death during the germinal center reaction. 26 Such observations, along with our own, imply the existence of a conserved pathway linking antigen receptor activation to transcriptional regulation of Bim and Noxa.…”

Section: Discussionmentioning

confidence: 99%

“…Bim and Puma) causes more severe defects than loss of Bim alone. 24,30 Such observations indicate that Bim represents the major, but not the sole, apoptotic regulator of B-cell homeostasis.…”

mentioning

confidence: 99%

BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma

et al. 2015

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The BH3-Only Proteins Bim and Puma Cooperate to Impose Deletional Tolerance of Organ-Specific Antigens

Cited by 64 publications

References 48 publications

Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen

Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen

Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

BCR-signaling-induced cell death demonstrates dependency on multiple BH3-only proteins in a murine model of B-cell lymphoma

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