Driving Rel-iant Tregs toward an Identity Crisis

Li, Amy; Jacks, Tyler

doi:10.1016/j.immuni.2017.08.014

Cited by 4 publications

(5 citation statements)

References 11 publications

(11 reference statements)

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“…Next, IKKβ-dependent serine-phosphorylation and ubiquitin-dependent degradation of IκBα initiate canonical NF-κB dimer (p50/p65) activation and nuclear entry ( 17 ). Notably, p65 and c-Rel (encoded by Rela and Rel , respectively) drive the acquisition/maintenance of Treg identity (Gitr + CD25 + Foxp3 + ) and function ( 11 ). In contrast, the conditional deletion of RelB in Foxp3 + Tregs does not alter the number and function of this subset, even though the germline deletion of RelB induces autoimmunity and an expansion of Foxp3 + Tregs (Table 1 ), mainly due to T cell-extrinsic mechanisms ( 19 ).…”

Section: The Nf-κb Team In Treg Biologymentioning

confidence: 99%

“…During the development of nTregs inside the thymus, both the nuclear localization and activity of c-Rel and RelA have been described in the transition from CD4 + CD8 + (DP) to Treg precursors generation (CD25 hi Gitr hi Foxp3 − CD4 + ) ( 12 ). Elegant studies by Gosh et al demonstrated that canonical NF-κB members have unique but partially redundant roles in Treg biology, with c-Rel being critical for thymic Treg development and p65 essential for mature Treg identity and maintenance of immune tolerance ( 11 , 13 ). Indeed, c-Rel loss decreases the number of nTregs and the expression of Treg signature genes (Gitr, CD25, Foxp3) involved in the maintenance of Treg identity ( 11 ), whereas mice harboring the p65 ablation in Tregs develop a lethal autoimmune syndrome.…”

Section: Nf-κb: a Forward Player Of Tregs Activity In Cancermentioning

confidence: 99%

“…Elegant studies by Gosh et al demonstrated that canonical NF-κB members have unique but partially redundant roles in Treg biology, with c-Rel being critical for thymic Treg development and p65 essential for mature Treg identity and maintenance of immune tolerance ( 11 , 13 ). Indeed, c-Rel loss decreases the number of nTregs and the expression of Treg signature genes (Gitr, CD25, Foxp3) involved in the maintenance of Treg identity ( 11 ), whereas mice harboring the p65 ablation in Tregs develop a lethal autoimmune syndrome. However, in the tumor context, the same group demonstrated that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs.…”

Section: Nf-κb: a Forward Player Of Tregs Activity In Cancermentioning

confidence: 99%

“…However, we demonstrated that the Notch3 hyperactivation in the N3-ICtg murine model of T-ALL requires PKCθ signals to upregulate Foxp3 core-promoter and to regulate Foxp3 + T-cell generation and suppressive function ( 14 ). Therefore, Notch3 and PKCθ converge on the hyperactivation of the canonical NF-κB pathway that rules over the developmental aspects and the activity of Tregs in the tumor microenvironment ( 11 ). Interestingly, constitutive NF-κB activation in two different CYLD -deficient murine models enhances Foxp3 expression and increases the total amount of Foxp3 + Tregs in the thymus and lymph nodes ( 44 , 105 ).…”

Section: Notch3 and Nf-κb Kick-starters In Foxp3 Promoter Activationmentioning

confidence: 99%

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Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

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Section: The Nf-κb Team In Treg Biologymentioning

confidence: 99%

Section: Nf-κb: a Forward Player Of Tregs Activity In Cancermentioning

confidence: 99%

Section: Nf-κb: a Forward Player Of Tregs Activity In Cancermentioning

confidence: 99%

Section: Notch3 and Nf-κb Kick-starters In Foxp3 Promoter Activationmentioning

confidence: 99%

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Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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“…REL is one of the NF-κB family members required for the development of progenitor Tregs or the development of mature Tregs. A xanthine derivative called PTXF (pentoxifylline) has specific and dose-dependent effects on REL and exhibits competitive and nonselective phosphodiesterase inhibitory activity ( 62 ). Ghosh et al demonstrated that in a mouse model of melanoma inhibition of C-Rel by PTXF, similar to genetic deletion of C-Rel, reduced Tregs and improved antitumor response ( 63 ).…”

Section: Treg-based Therapies In Cancermentioning

confidence: 99%

Regulating the regulatory T cells as cell therapies in autoimmunity and cancer

Hosseinalizadeh,

Rabiee,

Eghbalifard

et al. 2023

Front. Med.

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Regulatory T cells (Tregs), possess a pivotal function in the maintenance of immune homeostasis. The dysregulated activity of Tregs has been associated with the onset of autoimmune diseases and cancer. Hence, Tregs are promising targets for interventions aimed at steering the immune response toward the desired path, either by augmenting the immune system to eliminate infected and cancerous cells or by dampening it to curtail the damage to self-tissues in autoimmune disorders. The activation of Tregs has been observed to have a potent immunosuppressive effect against T cells that respond to self-antigens, thus safeguarding our body against autoimmunity. Therefore, promoting Treg cell stability presents a promising strategy for preventing or managing chronic inflammation that results from various autoimmune diseases. On the other hand, Tregs have been found to be overactivated in several forms of cancer, and their role as immune response regulators with immunosuppressive properties poses a significant impediment to the successful implementation of cancer immunotherapy. However, the targeting of Tregs in a systemic manner may lead to the onset of severe inflammation and autoimmune toxicity. It is imperative to develop more selective methods for targeting the function of Tregs in tumors. In this review, our objective is to elucidate the function of Tregs in tumors and autoimmunity while also delving into numerous therapeutic strategies for reprogramming their function. Our focus is on reprogramming Tregs in a highly activated phenotype driven by the activation of key surface receptors and metabolic reprogramming. Furthermore, we examine Treg-based therapies in autoimmunity, with a specific emphasis on Chimeric Antigen Receptor (CAR)-Treg therapy and T-cell receptor (TCR)-Treg therapy. Finally, we discuss key challenges and the future steps in reprogramming Tregs that could lead to the development of novel and effective cancer immunotherapies.

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