PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr

Xie, Chun; Patel, Rahul; Wu, Tianfu; Zhu, Jiankun; Henry, Tamika; Bhaskarabhatla, Madhavi; Samudrala, Renuka; Tus, Katalin; Gong, Yimei; Zhou, Hui; Wakeland, Edward K.; Zhou, Xin J.; Mohan, Chandra

doi:10.1093/intimm/dxm017

Cited by 31 publications

(26 citation statements)

References 43 publications

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“…S6 is phosphorylated downstream of the AKT/mTOR pathway and integrates multiple signals, including those of the MAPK pathway (13,14). Sustained activation of T cells, regardless of the initiating trigger, is associated with S6 kinase activity (34)(35)(36). The higher phosphorylation state of S6 in clone 2E2 is in accord with these data.…”

Section: Discussionsupporting

confidence: 53%

Trogocytosis Is a Gateway to Characterize Functional Diversity in Melanoma-Specific CD8+ T Cell Clones

Uzana

Eisenberg

Sagi

et al. 2012

The Journal of Immunology

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Trogocytosis, the transfer of membrane patches from target to immune effector cells, is a signature of tumor–T cell interaction. In this study, we used the trogocytosis phenomenon to study functional diversity within tumor-specific T cell clones with identical TCR specificity. MART-126–35–specific CD8 T cell clones, which differed in their trogocytosis capacity (low [2D11], intermediate [2G1], high [2E2]), were generated from melanoma patients. Functional evaluation of the clones showed that the percentage of trogocytosis-capable T cells closely paralleled each clone’s IFN-γ and TNF-α production, lysosome degranulation, and lysis of peptide-pulsed targets and unmodified melanoma. The highly cytotoxic 2E2 clone displayed the highest TCR peptide binding affinity, whereas the low-activity 2D11 clone showed TCR binding to peptide-MHC in a CD8-dependent manner. TCR analysis revealed Vβ16 for clones 2E2 and 2G1 and Vβ14 for 2D11. When peptide-affinity differences were bypassed by nonspecific TCR stimulation, clones 2E2 and 2D11 still manifested distinctive signaling patterns. The high-activity 2E2 clone displayed prolonged phosphorylation of ribosomal protein S6, an integrator of MAPK and AKT activation, whereas the low-activity 2D11 clone generated shorter and weaker phosphorylation. Screening the two clones with identical TCR Vβ by immunoreceptor array showed higher phosphorylation of NK, T, and B cell Ag (NTB-A), a SLAM family homophilic receptor, in clone 2E2 compared with 2G1. Specific blocking of NTB-A on APCs markedly reduced cytokine production by CD8 lymphocytes, pointing to a possible contribution of NTB-A costimulation to T cell functional diversity. This finding identifies NTB-A as a potential target for improving anti-cancer immunotherapy.

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Section: Discussionsupporting

confidence: 53%

Trogocytosis Is a Gateway to Characterize Functional Diversity in Melanoma-Specific CD8+ T Cell Clones

Uzana

Eisenberg

Sagi

et al. 2012

The Journal of Immunology

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“…The molecular mechanisms responsible for the mTOR‐dependent activation of NOX and NF‐κB in response to BCAA are unknown and this is a limitation of our study. However, other authors have also found a role for mTOR in oxidative stress generation40, 41 or NF‐κB activation in response to different stimuli or pathological conditions 42, 43. Besides mTORC1, BCAA trigger several signalling responses via the activation of AMPK, which plays a role in cellular energy homoeostasis.…”

Section: Discussionmentioning

confidence: 99%

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Zhenyukh

González‐Amor

Rodrigues-Díez

et al. 2018

J Cellular Molecular Medi

103

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Branched‐chain amino acids (BCAA: leucine, isoleucine and valine) are essential amino acids implicated in glucose metabolism and maintenance of correct brain function. Elevated BCAA levels can promote an inflammatory response in peripheral blood mononuclear cells. However, there are no studies analysing the direct effects of BCAA on endothelial cells (ECs) and its possible modulation of vascular function. In vitro and ex vivo studies were performed in human ECs and aorta from male C57BL/6J mice, respectively. In ECs, BCAA (6 mmol/L) increased eNOS expression, reactive oxygen species production by mitochondria and NADPH oxidases, peroxynitrite formation and nitrotyrosine expression. Moreover, BCAA induced pro‐inflammatory responses through the transcription factor NF‐κB that resulted in the release of intracellular adhesion molecule‐1 and E‐selectin conferring endothelial activation and adhesion capacity to inflammatory cells. Pharmacological inhibition of mTORC1 intracellular signalling pathway decreased BCAA‐induced pro‐oxidant and pro‐inflammatory effects in ECs. In isolated murine aorta, BCAA elicited vasoconstrictor responses, particularly in pre‐contracted vessels and after NO synthase blockade, and triggered endothelial dysfunction, effects that were inhibited by different antioxidants, further demonstrating the potential of BCAA to induce oxidative stress with functional impact. In summary, we demonstrate that elevated BCAA levels generate inflammation and oxidative stress in ECs, thereby facilitating inflammatory cells adhesion and endothelial dysfunction. This might contribute to the increased cardiovascular risk observed in patients with elevated BCAA blood levels.

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“…These studies strongly suggest that members of the NF-kB/Rel family perform nonoverlapping functions, and that loss-of-function mutations of NF-kB/Rel genes cannot be fully compensated by other members of same family. Recent evidence suggests that perturbed signals (the M55V substitution in SUMO4 [45], PI3K-AKT hypersignaling [46], increased TNF-a [47]) all lead to the elevated activation of NF-kB and have been associated with lymphoproliferative or autoimmune diseases. Since constitutive expression of Foxp3 is essential for Treg function, and the function of NF-kB is also attenuated by physical interaction with Foxp3 [48], it would be interesting to investigate the role of NF-kB isoforms in the expression of Foxp3.…”

Section: Tgf-b1 Attenuates Nf-jb Binding On Foxp3 Promotermentioning

confidence: 99%

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

et al. 2009

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The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3 + Treg cells can be generated from naïve T cells ex vivo, following TCR and TGF-b1 stimulations. However, the molecular contributions from the different arms of these pathways leading to Foxp3 expression are not fully understood. TGF-b1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-b1-induced-Treg generation from Smad3 À/À mice is markedly reduced and abolished by inactivating Smad2. In the TCR pathway, deletion of Bcl10, which activates NF-jB, markedly reduces both IL-2 and Foxp3 production. However, partial rescue of Foxp3 expression occurs on addition of exogenous IL-2. TGF-b1 significantly attenuates NF-jB binding to the Foxp3 promoter, while inducing Foxp3 expression. Furthermore, deletion of p50, a NF-jB subunit, results in increased Foxp3 expression despite a decline in the IL-2 production. We posit several TCR-NF-jB pathways, some increasing (Bcl10-IL-2-Foxp3) while others decreasing (p50-Foxp3) Foxp3 expression, with the former predominating. A better understanding of Foxp3 regulation could be useful in dissecting the cause of Treg dysfunction in several autoimmune diseases and for generating more potent TGF-b1-induced-Treg cells for therapeutic purposes. There are reports documenting a reduction in the number or function of Treg cells in patients with numerous autoimmune diseases, including diabetes, rheumatoid arthritis, psoriasis, myasthenia gravis or sarcoidosis [12][13][14][15]. Thus, one possible way for restoration of self-tolerance in these patients could be by the infusion of Treg cells having an increased ability to control ongoing autoimmune destruction. Due to the limited availability of nTreg cells, in vitro generated iTreg cells may serve as an alternative source of Treg cells for therapeutic purposes. There is strong evidence that these Foxp3 + iTreg cells can prevent/delay the development of Type 1 Diabetes in the NOD mice [16,17]. Hence, the regulation of Foxp3 expression during iTreg generation is of considerable interest. Relatively little is known about the regulation of Foxp3 in the periphery. The essential roles of IL-2, TGF-b and TCR signaling in iTreg generation have been established [11,[18][19][20]. However, it is unclear which particular arms in each of these pathways are important in FoxP3 regulation. TGF-b1 is a pluripotent cytokine that has pronounced effects on T-cell-mediated immune suppression as well as on the control of autoimmunity. The binding of TGF-b1 to its receptor complex activates the intracellular kinase domain of TGF-bRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non-Smad proteins (Smad-independent pathway) [21]. After forming a heterodimer with phosphorylated Smad4, activated Smad2 and Smad3 translocate to the nucleus where they regulate TGF-b1-dependent gene expression. The generation of nTreg cells from the thymus of TGF...

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PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr

Cited by 31 publications

References 43 publications

Trogocytosis Is a Gateway to Characterize Functional Diversity in Melanoma-Specific CD8+ T Cell Clones

Trogocytosis Is a Gateway to Characterize Functional Diversity in Melanoma-Specific CD8+ T Cell Clones

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

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