Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

Liu, Xindong; Wang, Yun; Lu, Huiping; Li, Jing; Yan, Xiaowei; Xiao, Minglu; Hao, Jun; Alekseev, Andrei; Khong, Hiep; Chen, Tenghui; Huang, Rui; Wu, Jin; Zhao, Qi-Wen; Wu, Qi; Xu, Senlin; Wang, Xiaohu; Jin, Wei; Yu, Shanshan; Wang, Yan; Wei, Lai; Wang, Aibo; Zhong, Bo; Ni, Ling; Liu, Xiaolong; Nurieva, Roza; Ye, Lilin; Tian, Qiang; Bian, Xiu Wu; Dong, Chen

doi:10.1038/s41586-019-0979-8

Cited by 356 publications

(393 citation statements)

References 30 publications

(48 reference statements)

Supporting

Mentioning

348

Contrasting

Order By: Relevance

“…158,159 This raises the possibility that Nr4a family members collectively may play additional undiscovered roles in B cell tolerance. Indeed, recent work shows that the Nr4a family plays a role in down-modulating T cell responses to chronic antigen stimulation by engaging the exhaustion program in CD8 T cells and the "anergy program" in CD4 T cells that receive signal one without co-stimulation.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

“…Indeed, recent work shows that the Nr4a family plays a role in down-modulating T cell responses to chronic antigen stimulation by engaging the exhaustion program in CD8 T cells and the "anergy program" in CD4 T cells that receive signal one without co-stimulation. 158,159 This raises the possibility that Nr4a family members collectively may play additional undiscovered roles in B cell tolerance. To unmask redundancy among this three-member family, conditional elimination of multiple family members will be necessary.…”

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

See 1 more Smart Citation

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

View full text Add to dashboard Cite

Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self-reactive B cell receptors (BCRs) from populating the periphery.Despite this, modest self-reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77-eGFP, expression of which scales with the degree of self-reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self-reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance. K E Y W O R D Sanergy, B cell, IgD, IgM, Nur77/Nr4a1, tolerance Previous work from our laboratory exploiting an in vivo reporter of antigen recognition, Nur77-eGFP BAC Tg, addresses this important point ( Figure 1A). 15 GFP expression in this reporter line is under the control of the regulatory region of Nr4a1/ Nur77. Nr4a1-3 encode a small family of orphan nuclear hormone receptors which were originally cloned as signal-dependent primary response genes (also known as immediate-early genes), and are highly upregulated by a range of mitogens, including antigen receptor stimulation. [16][17][18] Consequently, antigen stimulation rapidly triggers reporter expression in B and T cells in vitro ( Figure 1B), and GFP is also induced by infection or immunization in antigen-specific lymphocytes in

show abstract

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

Section: Con Clus I On S and Future Direc Tionsmentioning

confidence: 99%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

View full text Add to dashboard Cite

show abstract

“…More recent studies of the Nr4a family have found that nuclear factor of activated T cells (NFAT) (Martinez et al, 2015) and Nr4a receptors (Mognol et al, 2017;Scott-Browne et al, 2016) are intimately linked to the development of CD8 + T cell exhaustion, suggesting that NFAT and Nr4a family members may cooperate during chronic antigen stimulation to adapt T cell programmes. Indeed, Nr4a family members have been shown to limit chimeric antigen receptor (CAR) T cell function in solid tumours and that Nr4a1 may be a key mediator of T cell dysfunction through binding and repressing expression of the activator protein one (AP-1) transcription factor (Liu et al, 2019). Nr4a family member function is complex since they can also promote CD8 + T cell exhaustion through cooperation with other transcription factors such as thymocyte selection-associated high mobility group box protein (TOX) and TOX2 .…”

Section: Introductionmentioning

confidence: 99%

Differential Nr4a1 and Nr4a3 expression discriminates tonic from activated TCR signalling events in vivo

Jennings

Elliot

Thawait

et al. 2019

Preprint

View full text Add to dashboard Cite

Nr4a gene family members are activated by T cell receptor (TCR) signalling and play key roles in Regulatory T cell differentiation and have also been implicated in promoting T cell exhaustion in cancer. The precise signalling pathways that govern their transcription, however, remain unclear. Here we utilise Nr4a3-Tocky mice to elucidate the signalling pathways that govern Nr4a1, 2 and 3 expression in response to physiological stimulation of CD4 + and CD8 + T cells. Our findings reveal that Nr4a1-3 are Src family kinase-dependent. Moreover, Nr4a2 and Nr4a3 are abolished by calcineurin inhibitors and bind NFAT1, highlighting a necessary role for NFAT in the control of Nr4a2 and Nr4a3. Interestingly, the NFAT pathway is redundant for Nr4a1 activation, but all three Nr4a members require ERK signalling for optimal expression. Analysis of T cells expressing constitutively active NFAT1 reveals that NFAT1 alone is sufficient to induce expression of Nr4a2 and Nr4a3, but not Nr4a1.These findings further our understanding of Nr4a regulation, highlighting key differences in the sensitivity of Nr4a1 and Nr4a3 to distal TCR signalling pathways.

show abstract

“…5) revealed that the metabolically-repressed CD39/PD1 cells were excluded from the tumor-immune boundary, a complex multicellular structure known to regulate immune function 76 . Importantly, while surface expression of CD39 and PD1 indicate T cell exhaustion/dysfunction, they can be expressed more broadly, driving the recent identification and integration of molecular regulators such as TOX 100-104 , NR4A 105,106 and TCF1 75,107 as more definitive indicators of immune cell dysfunction. Taken together, the here identified association of metabolic phenotype with CD39/PD1 expression and TCF1 downregulation, as well as the tumor-36 specific expansion of this metabolic subset in combination with its exclusion from the tumorimmune boundary suggest that incorporation of metabolic profiling to identify functionally diverse T cell states could further improve clinical stratification, e.g.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

Hartmann

Mrdjen

McCaffrey

et al. 2020

Preprint

View full text Add to dashboard Cite

Cellular metabolism regulates immune cell activation, differentiation and effector functions to the extent that its perturbation can augment immune responses. However, the analytical technologies available to study cellular metabolism lack single-cell resolution, obscuring metabolic heterogeneity and its connection to immune phenotype and function. To that end, we utilized high-dimensional, antibody-based technologies to simultaneously quantify the single-cell metabolic regulome in combination with phenotypic identity. Mass cytometry (CyTOF)-based application of this approach to early human T cell activation enabled the comprehensive reconstruction of the coordinated metabolic remodeling of naïve CD8 + T cells and aligned with conventional bulk assays for glycolysis and oxidative phosphorylation. Extending this analysis to a variety of tissue-resident immune cells revealed tissue-restricted metabolic states of human cytotoxic T cells, including metabolically repressed subsets that expressed CD39 and PD1 and that were enriched in colorectal carcinoma versus healthy adjacent tissue. Finally, combining this approach with multiplexed ion beam imaging by time-of-flight (MIBI-TOF) demonstrated the existence of spatially enriched metabolic neighborhoods, independent of cell identity and additionally revealed exclusion of metabolically repressed cytotoxic T cell states from the tumor-immune boundary in human colorectal carcinoma. Overall, we provide an approach that permits the robust approximation of metabolic states in individual cells along with multimodal analysis of cell identity and functional characteristics that can be applied to human clinical samples to study cellular metabolism how it may be perturbed to affect immunological outcomes.

show abstract

Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

Cited by 356 publications

References 30 publications

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Differential Nr4a1 and Nr4a3 expression discriminates tonic from activated TCR signalling events in vivo

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

Contact Info

Product

Resources

About