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Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted T cell fate

ABSTRACT: This study aims to define how Id2 and Id3 regulate exhausted CD8+ T cell fate. We found that Id2 deletion reduced the Tex-eff population, whereas Id3 ablation in CD4-Cre mice diminished Tpex cells, indicating subset-specific roles for Id2 and Id3. Mechanistically, E2A is a major target of Id2/3, and Runx3 interacts with E2A. Pulldown of Id2/3 recovered both E2A and Runx3, supporting an Id2/3?E2A?Runx3 regulatory complex. To map the genomic occupancy of Id2 and Id3, we expressed 3×T7-tagged Id2 or Id3 in in vitro-primed CD45.2+ P14 cells, adoptively transferred these cells into CD45.1 recipient mice, and infected the recipients with LCMV Clone 13. On day 6 post-infection, Tex-eff and Tpex cells were isolated for T7 CUT&RUN to define Id2 binding in Tex-eff cells and Id3 binding in Tpex cells, with the empty T7 vector backbone used as a negative control.

ORGANISM(S): Mus musculus

PROVIDER: GSE310322 | GEO | 2026/04/20

REPOSITORIES: GEO

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Id proteins suppress E2A-driven iNKT cell development prior to TCR selection [RNA-seq_new]

Project description:Id proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give rise to these distinct cell fates. Here we report that in the absence of Id2 and Id3 proteins, E2A prematurely activates genes critical for the iNKT cell lineage prior to TCR expression. Lack of Id proteins also promotes a biased TCR rearrangement in favor of iNKT cell fate prior to selection at the CD4+CD8+ double positive (DP) stage. Enhanced iNKT development in Id3-deficient mice lacking γδNKT cells suggests that Id3 regulates the lineage competition between these populations. RNA-Seq analysis establishes E2A as the transcriptional regulator of both iNKT and γδNKT development. In the absence of pre-TCR signaling, Id2/Id3 deletion gives rise to a large population of iNKT cells and a unique innate-like DP population, despite the block in conventional αβ T cell development. The transcriptional profile of these unique DP cells reflects enrichment of innate-like signature genes, including PLZF (Zbtb16) and Granzyme A (Gzma). Results from these genetic models and genome-wide analyses suggest that Id proteins suppress E2A-driven innate-like T cell programs prior to TCR selection to enforce predominance of conventional T cells.

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Id proteins suppress E2A-driven iNKT cell development prior to TCR selection [ChIP-seq]

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Id proteins suppress E2A-driven iNKT cell development prior to TCR selection [RNA-seq]

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Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted T cell fate

Project description:The goal of this study is to determine how transcription cofactors, Id2 and Id3, mediate differential regulation of exhausted CD8 T cell fate decision and differentiation at the early stage of responses to chronic viral infection.

2026-04-15 | GSE310256 | GEO

Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

Project description:It is established that E2A and its antagonist, Id3, modulate developmental progression at the pre-TCR and TCR checkpoints. Here we show at a global scale how E2A promotes commitment to the T cell lineage and how pre-TCR mediated signalling affects E2A genome-wide occupancy. We find aberrant development of CD4 memory-like and TFH-like cells, T-B cell conjugates and, remarkably, B cell follicles in Id3-/-thymi. We also find that Id3-/-CD4 splenocytes exhibit increased numbers of TFH-like cells. We propose a model in which Id3 modulates the naive versus effector/memory cell fate. Collectively, these data show how E2A acts globally to orchestrate T-lineage development and that Id3 antagonizes E2A activity beyond the pre-TCR checkpoint to enforce the naive T cell fate.

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A genetic circuitry linking Id-proteins (Id2 and Id3) and the AKT-FOXO-mTORC1 axis to suppress innate-variant TFH cell development, maintain T cell quiescence and prevent lymphomagenesis.

Project description:It is now well established that the E- and Id-protein axis regulates multiple steps in lymphocyte development. However, it remains unknown as to how E- and Id-proteins mechanistically enforce and maintain the naïve T cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate-variant TFH cells. Innate-variant TFH cells required MHC Class I-like signalling and were associated with germinal center B cell development. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion and activation. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities with genetic deficiencies associated with Burkitt lymphoma. We propose that in response to antigen receptor and/or cytokine signaling the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hifa and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation. RNA-seq data of 5 of wild type CD4SP cells, 3 of wild type Tfh cells, 3 of Id3-/- CD4SP cells, 3 of Id2-/-Id3-/-(dKO) CD4SP cells, and 6 of Id2-/-Id3-/- lymphoma cells.

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Contrasting functions of CD73 and adenosine in CD8+ T cell exhaustion

Project description:T cell exhaustion is a state of functional decline in T cells, driven by chronic antigen exposure and inhibitory signals within the tumor microenvironment. Exhausted CD8+ T cells (Tex) derive from precursor exhausted T cells (Tpex), a self-renewing population responsible for the proliferative burst observed in anti-PD-1 therapies. Exhausted cells are exposed to adenosine in the tumor, yet the role of the CD73/adenosine axis and Tpex/Tex differentiation remains unclear. Using an in vitro model for CD8+ T cell exhaustion, we found that CD73 expression increased during Tpex formation and that its expression is negatively correlated with Tex generation. CD73-deficient (CD73KO) CD8⁺ T cells showed impaired activation and reduced progression to Tex. Moreover, we demonstrated that CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR) and the differentiation into IFNγ/TNFα-producing Tex cells. RNAseq analysis of exhausted CD73KO CD8+ T cells showed a more stem-like transcriptomic profile and enrichment in genes associated with the immune response than their WT counterpart. In vivo, co-transfer of naïve CD73 KO and WT tumor antigen-specific CD8⁺ T cells into tumor-bearing mice showed increased Tpex frequency and numbers among CD73KO cells in tumors. Conversely, in vitro exhaustion in the presence of A2AR agonists decreased Tex frequency and activation/exhaustion markers, while increasing CD73 and CD62L, markers associated with stemness. Supporting this, A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation. Altogether, our data suggest CD73 promotes Tpex-to-Tex differentiation, whereas adenosine-A2AR signaling supports Tpex maintenance in the tumor microenvironment.

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Opposing roles of E2A and Id3 that orchestrate and enforce the naive T cell fate

2011-07-31 | E-GEOD-30518 | biostudies-arrayexpress

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