Immature CD4+CD8+ Thymocytes and Mature T Cells Regulate Nur77 Distinctly in Response to TCR Stimulation

Cunningham, Nicole; Artim, Stephen C.; Fornadel, Christen; Sellars, MacLean; Edmonson, Samuel G.; Scott, Grant N.; Albino, Frank P.; Mathur, Akriti; Punt, Jennifer A.

doi:10.4049/jimmunol.177.10.6660

Cited by 50 publications

(51 citation statements)

References 45 publications

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“…Overexpression studies using myr-Akt show that activated Akt1 leads to enhanced Erk phosphorylation, providing evidence for cross-talk between the pathways (25). Indeed, the pathways may converge on similar targets in the thymus (26); however, there is no evidence that the MAPK signaling pathway depends on Akt activation. The molecular mechanism that allows for the proliferative burst at the ␤-selection checkpoint likely integrates survival, mitotic, and metabolic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

Juntilla

Wofford

Birnbaum

et al. 2007

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

125

141

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The ␤-selection checkpoint in ␣␤T lymphocyte development occurs at the double negative (DN) 3 (CD4 ؊ CD8 ؊ CD25 ؉ c-kit ؊ ) stage, when further differentiation requires a signal from the newly rearranged TCR ␤ chain. Thymocytes with mutations in key signaling molecules in the phosphatidylinositol 3-kinase-Akt pathway manifest defects in survival, proliferation, and differentiation past the ␤-selection checkpoint. However, little information is available regarding the role of Akt itself in thymocyte development. In this study, we explore the role of the two Akt isoforms most highly expressed in the thymus, Akt1 and Akt2, in early T cell development. Using several complementary approaches, we find that deletion of Akt1 results in only minor defects in thymocyte development. The Akt1 ؊/؊ Akt2 ؊/؊ thymocytes manifest a severe developmental block at the DN3 stage and ultimately fail to repopulate the T cell compartment of an irradiated host. Further, we show that Akt1 ؊/؊ Akt2 ؊/؊ DN3 cells have decreased glucose uptake and die in response to TCR stimulation in vitro. Study of thymocytes from the genetically altered mice suggests that the cause of the developmental defect is due to apoptosis, partially caused by decreased cellular growth and metabolism at the DN3 stage. Our results show that Akt protects thymocytes from cell death during the ␤-selection checkpoint.apoptosis ͉ metabolism ͉ thymic development

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Section: Discussionmentioning

confidence: 99%

Akt1 and Akt2 are required for αβ thymocyte survival and differentiation

Juntilla

Wofford

Birnbaum

et al. 2007

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

125

141

View full text Add to dashboard Cite

show abstract

“…We turned to transcriptional profiling for clues about Nr4a1's mechanism of action in both apoptosis and Treg differentiation. Profiles from WT or Nr4a1-deficient thymocytes were compared primarily in two different settings: (i) DPs from age/sex-matched WT or Nr4a1KO stimulated in vitro for 3 h with plate-bound anti-TCRβ/CD28/CD2, conditions used by others to mimic negative selection and under which Nr4a1 and Bim are rapidly induced (20); this short response time should bring forth Nr4a1's direct transcriptional footprint; (ii) DP and CD4 + CD25 − Vα2 hi Vβ5 hi SP thymocytes from adult OTII and OTII/RIP-mOVA transgenic mice for a footprint of Nr4a1 in vivo under steady-state conditions of antigen-induced clonal deletion. The latter in vivo datasets should show, under more physiological conditions, the more integrated (direct and indirect) influence of Nr4a1 in cells that survive apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…On culture day 3, BDC-specific mimotope peptide (BDCmi, peptides 1,040-1,063) (25) was added to culture media, and lobes were analyzed 16 h later. For in vitro thymocyte stimulation, single-cell thymocyte suspensions were incubated at 5 × 10 6 cells/mL for 3 h at 37°C with plates precoated with anti-TCRβ (10 μg/mL), anti-CD2 (10 μg/mL), and anti-CD28 (50 μg/mL) as described (20). Cell sorting for microarray RNA preparation and hybridization to Affymetrix MoGene 1.0ST and RMA normalization were performed as described (49).…”

Section: Methodsmentioning

confidence: 99%

“…Nr4a1 transcripts are differentially induced in double-positive (DP) and single-positive (SP) thymocytes (20) and in B6 vs. non-obese diabetic (NOD) thymocytes during negative selection, where lower levels of Nr4a1 mRNA correlate with the apparently impaired clonal deletion of NOD mice (21,22). Nr4a1 transcripts also appear as part of the proapoptotic program in T lymphocytes during times of cellular stress such as steroid treatment or oxygen deprivation (12,13).…”

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confidence: 99%

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Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion

Fassett

Jiang

D’Alise

et al. 2012

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

105

118

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Immature thymocytes expressing autoreactive T-cell receptors (TCR) can adopt differing cell fates: clonal deletion by apoptosis or deviation into alternative lineages such as FoxP3 + regulatory T cells (Treg). We revisited the role of the transcription factor Nr4a1 (Nur77), an immediate-early response gene induced by TCR engagement. Nr4a1KO mice show clear quantitative defects in antigen-induced clonal deletion. The impact of the Nr4a1 deletion is not enhanced by deletion of the proapoptotic factor Bim. In addition, Nr4a1 curtails initial differentiation into the Treg lineage in TCR transgenic mice and in nontransgenic mice. Transcriptional profiling of Nr4a1KO thymocytes under selection conditions reveals that Nr4a1 activates the transcription of several targets, consistent with these diverse actions: (i) Nr4a1 partakes in the induction of Bim after TCR triggering; (ii) perhaps paradoxically, Nr4a1 positively controls several transcripts of the Treg signature, in particular Ikzf2 and Tnfrsf9; (iii) consistent with its prosurvival and metabolic role in the liver, Nr4a1 is also required for the induction by TCR of a coordinated set of enzymes of the glycolytic and Krebs cycle pathways, which we propose may antagonize Treg selection as does activation of mTOR/Akt. Thus, Nr4a1 appears to act as a balancing molecule in fate determination at a critical juncture of T-cell differentiation.glycolysis | immune tolerance | thymus | nuclear receptor A hallmark of the adaptive immune system is its ability to respond to the infinite repertoire of potential pathogens to which it might someday be exposed, but the undirected process of antigen receptor rearrangement in thymocytes generates receptors that are reactive to self and hence are potentially dangerous. Fledgling T cells carrying a nascent T-cell receptor (TCR) must undergo a rigorous process of negative selection, during which cells expressing a self-reactive TCR are eliminated by induced apoptosis or deviated to alternative differentiation pathways in which self-reactivity is defused [NKT, CD8αα, or FoxP3 + Triggering of mitochondrial apoptosis by signaling cascades downstream from the TCR is clearly established. Bim and Bax/ Bak, proapoptotic members of the mitochondrial apoptosis pathway, are essential for efficient negative selection (2, 3), but this may not be the sole mechanism. Early experiments involving blockade of RNA or protein synthesis suggested that negative selection is both transcription and translation dependent (4). Indeed, the transcription factor Nr4a1 has been implicated in negative selection (5, 6). An orphan member of the nuclear receptor superfamily and the Nr4a1/Nr4a2/Nr4a3 subfamily, Nr4a1 is a transcriptional activator, but can also promote mitochondrial apoptosis. In both tumor cell lines and thymocytes undergoing negative selection, Nr4a1 undergoes phosphorylation-dependent export from the nucleus to the mitochondria, where it conformationally alters Bcl-2 to promote apoptosis (7-10). Nr4a1 is associated with apoptosis in a number of phys...

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“…Nur77 was initially thought to upregulate factors that mediate apoptosis since the transcriptional activity of Nur77 correlates with its ability to induce thymocyte death (Kuang et al 1999). Furthermore, Nur77 has been shown to remain in the nucleus of stimulated thymocytes, while nuclear export of Nur77 in mature T cells is thought to protect them from apoptosis (Cunningham et al 2006). However, the only target genes of Nur77 with known apoptotic function are those involved in the extrinsic apoptosis pathway (Rajpal et al 2003).…”

Section: Programmed Cell Death In T Cell Development 139mentioning

confidence: 99%