Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells

O’Leary, Claire E.; Riling, Christopher; Spruce, Lynn A.; Ding, Hua; Kumar, Suresh; Deng, Guoping; Liu, Yuhong; Seeholzer, Steven H.; Oliver, Peter

doi:10.1038/ncomms11226

Cited by 30 publications

(40 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ndfip1-deficient CD4+ T cells secrete excess IL-4242829 and this can impact the differentiation of alternate cell fates or affect the activation state of T cells. For Th17 cells, IL-4 has been shown to both promote or inhibit their differentiation27313335.…”

Section: Resultsmentioning

confidence: 99%

“…This study focused predominantly on Ndfip1, an activator of Itch catalytic activity24284849. It has been shown that the loss of Ndfip1 globally, or following conditional deletion in T cells, causes spontaneous autoinflammatory disease that is associated with high numbers of activated CD4 T cells, increased numbers of Th1, Th2, and Th17 cells, and premature death24262729.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that while Itch may require Ndfip1 for its activation in Th17 cells, it may also rely on other mechanisms of activation. We recently found that Ndfip2 has similar functions to Ndfip1 and can also activate Itch and related E3 ubiquitin ligases in CD4 T cells28. It remains to be seen whether Ndfip2 may also work with Itch to limit Th17 cell proinflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

“…Nedd4-family interacting protein 1 (Ndfip1) is a protein that activates the catalytic function of members of the Nedd4 family. Mice deficient in Ndfip1 protein develop a spontaneous inflammatory disease marked by an increase in the frequency of several subsets of CD4+ T cells including CD44+ T cells242526, IL-17A+ Th17 cells27, IFNγ+ CD4 T cells2628 and IL-4+ Th2 cells242829 at mucosal barrier surfaces such as the lungs, GI tract, and the skin. The predominant defect observed in these mice –namely the increase in Th2 cells- occurs because Ndfip1 is not available to activate Itch, an E3 ligase that is required for polyubiquitylation and degradation of the transcription factor JunB.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Layman¹,

Sprout²,

Phillips³

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Layman¹,

Sprout²,

Phillips³

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…NDFIP1 binds to and activates HECT-type E3 ubiquitin ligases (Mund and Pelham, 2009; Riling et al, 2015), thereby triggering ubiquitin-medi- ated degradation of key T cell differentiation regulators, including JUNB, RORγt, and JAK1 (Layman et al, 2017b; O’Leary et al, 2016; Oliver et al, 2006). In T cells, NDFIP1 primarily recruits and activates the HECT-type E3 ligase ITCH (Oliver et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

et al. 2018

View full text Add to dashboard Cite

SUMMARY Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints.

show abstract

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Pan

Shu

et al. 2023

Advanced Science

View full text Add to dashboard Cite

High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC).There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN-𝜸-induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain-binding protein 1-like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN-𝜸/JAK1/STAT1/PD-L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8 + T cell-mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD-L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient-derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

show abstract

Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells

Cited by 30 publications

References 60 publications

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Contact Info

Product

Resources

About