Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity

Gokhale, Ameya; Gangaplara, Arunakumar; Lopez-Occasio, Maria; Thornton, Angela M.; Shevach, Ethan M.

doi:10.1016/j.jaut.2019.06.011

Cited by 41 publications

(38 citation statements)

References 27 publications

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“…The immunosuppressive role of Treg cells is well known, which can lead to cancer progression. Destabilization of Treg cells by a deficiency of critical Treg-associated factors such as Nrp-1, SOCS1, EZH2, Eos or CARMA1 protects hosts from syngeneic tumor growth 20 , 21 , 31 – 33 . Recent studies have also revealed that upregulation of HIF-1α induces fragility in Treg cells having anticancer immunity 22 , 30 .…”

Section: Resultsmentioning

confidence: 99%

“…[15][16][17] ). There are reports that Treg cells can be reprogrammed into inflammatory cells in certain autoimmune diseases [18][19][20][21][22] . Recent studies have demonstrated that ex vivo expansion of Treg cells can be used to treat autoimmune diseases and transplantation rejection [23][24][25] .…”

mentioning

confidence: 99%

“…However, Treg cells contribute to immunosuppressive environments and are a major element inhibiting intratumor anticancer immunity [26][27][28] . Treg-selective deletion of essential Treg factors such as Neuropilin-1 (Nrp-1), suppressor of cytokine signaling 1 (SOCS1), enhancer of zeste homolog 2 (EZH2), Eos (IKzf4), or CARMA1 leads to Foxp3 downregulation and inflammatory cytokine secretion, conferring resistance to tumor growth in the host [20][21][22][29][30][31][32][33] .…”

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confidence: 99%

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HIF-2α is indispensable for regulatory T cell function

et al. 2020

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Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is controversial. Here, we show that Treg cell development is normal in mice with Foxp3-specific knockout (KO) of HIF-1α or HIF-2α. However, HIF-2α-KO (but not HIF-1α-KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2α-KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2α and HIF-1α, and that HIF-2α represses HIF-1α expression. HIF-1α is upregulated in HIF-2α-KO Treg cells and further deletion of HIF-1α restores the inhibitory function of HIF-2α-KO Treg cells. Mice with Foxp3-conditional KO of HIF-2α are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2α to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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HIF-2α is indispensable for regulatory T cell function

et al. 2020

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“…In contrast, our data from homeostatic proliferation studies, cardiac transplant experiments, and tumor models all point to a crit- ical loss of Treg function when Rcor1 -/mice were challenged by strong T cell activation in vivo. The apparent disconnect between minor effects in vitro and in vivo in Rcor1 -/mice under basal conditions compared with when subject to activating stimuli is not unusual, e.g., the ablation of Blimp1, Icos, IL-10, Ctla4, or Eos in Tregs does not affect their suppressive properties in vitro, but impairs their activation under stimulating conditions and their activities in vivo (36)(37)(38)(39)(40)(41), similarly to what occurred in our Rcor1 -/mice. These data and our related findings using bifunctional CoREST inhibitors in WT mice underscore the potential benefit of targeting this complex for therapeutic purposes, such as in cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

Xiong¹,

Wang²,

Giorgio³

et al. 2020

Journal of Clinical Investigation

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“…In contrast, Ikzf4 knock-down or knock-out drives loss of numerous Treg-specific genes and expression of Tconv-associated genes [57]. Consequently, mice with conditional ablation of Ikzf4 in Treg cells develop a lymphoproliferative and autoimmune syndrome starting 3 months after birth [59]. This loss of in vivo functionality also leads to impaired suppression of anti-tumor immunity, as shown by the increased T-cell infiltration and function and reduced burden of colon cancer in mutant animals [59].…”

Section: Eosmentioning

confidence: 99%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity

Cited by 41 publications

References 27 publications

HIF-2α is indispensable for regulatory T cell function

HIF-2α is indispensable for regulatory T cell function

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

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