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B cell leukemia co-opts a hematopoietic stem cell-CD4 T cell tolerance program that facilitates relapse [scATAC-Seq]

ABSTRACT: Despite advances in immune therapies, leukemic relapse is still a major obstacle to long-term survival. Using a murine model of B cell leukemia (B-ALL), we show that B-ALL co-opts a hematopoetic stem cell (HSC)-driven program to induce immune-suppressive type-1 regulatory (Tr1) CD4 T cells. The immune-suppressive function of Tr1s that protects healthy HSCs is utilized by B-ALL to evade T-cell surveillance. Using single-cell approaches, we show that B-ALL induces a Tr1 phenotype in all CD4 T cells irrespective of their initial polarization state. Unlike exhausted T cells, Tr1s do not have epigenetic silencing of effector cytokines. Both IL10R- and PDL1-blockade mitigate Tr1 expansion upon treatment with the tyrosine kinase inhibitor nilotinib. However, PDL1-blockade alone expands Th1-memory CD4s and effector CD8s that prevent relapse. We find a similar population of CD4 Tr1s in human B-ALL patients, which correlate with worse prognosis. Thus, B-ALL co-opts an HSC-driven program to induce Tr1s that suppress anti-leukemia T cell responses, which facilitates relapse.

ORGANISM(S): Mus musculus

PROVIDER: GSE262391 | GEO | 2025/12/31

REPOSITORIES: GEO

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B cell leukemia co-opts a hematopoietic stem cell-CD4 T cell tolerance program that facilitates relapse [CITE-Seq]

Project description:Despite advances in immune therapies, leukemic relapse is still a major obstacle to long-term survival. Using a murine model of B cell leukemia (B-ALL), we show that B-ALL co-opts a hematopoetic stem cell (HSC)-driven program to induce immune-suppressive type-1 regulatory (Tr1) CD4 T cells. The immune-suppressive function of Tr1s that protects healthy HSCs is utilized by B-ALL to evade T-cell surveillance. Using single-cell approaches, we show that B-ALL induces a Tr1 phenotype in all CD4 T cells irrespective of their initial polarization state. Unlike exhausted T cells, Tr1s do not have epigenetic silencing of effector cytokines. Both IL10R- and PDL1-blockade mitigate Tr1 expansion upon treatment with the tyrosine kinase inhibitor nilotinib. However, PDL1-blockade alone expands Th1-memory CD4s and effector CD8s that prevent relapse. We find a similar population of CD4 Tr1s in human B-ALL patients, which correlate with worse prognosis. Thus, B-ALL co-opts an HSC-driven program to induce Tr1s that suppress anti-leukemia T cell responses, which facilitates relapse.

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Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [scRNA-seq]

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Reproducible single cell annotation of programs underlying T cell subsets, activation states, and functions

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Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells

Project description:CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases. The transcriptome of human Tr1 cell clones to that of TH0 cell clones either unstimulated or stimulated for 6 and 16 h. Tr1 and TH0 cell clones were isolated from peripheral blood of 2 Healthy Donors (HDs). mRNA from T cell clones unstimulated (t0, n=4 Tr1 cell clones and n=10 TH0 cell clones) or stimulated with immobilized anti-CD3 and soluble anti-CD28 mAbs (6h and 16h, n=4 Tr1 cell clones and n=5 TH0 cell clones) was isolated. Differential expression of 28869 genes was investigated by whole transcript Affymetric chips.

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Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells

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Combination therapy with nilotinib and PDL1 blockade reverses CD4 T cell dysfunction and prevents relapse in acute B cell leukemia

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Gene expression of type 1 regulatory T (Tr1) cells

Project description:Purpose: To identify gene expression patterns in ex vivo isolated human Tr1 cells. Method: RNA sequencing of total mRNA. Results: Differential gene expression of Tr1 and non-Tr1 CD4+ T memory cells. Conclusions: ex vivo type 1 regulatory T cells have a distinct gene expression profile compared to non-Tr1 CD4+ T cell memory cells.

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IL-10 Receptor Signaling is essental for Tr1 cell function in vivo

Project description:Interleukin-10 (IL-10) is essential to maintain intestinal homeostasis. CD4+ T regulatory type 1 (TR1) cells produce large amounts of this cytokine and being therefore currently examined in clinical trials as T-cell therapy in patients with inflammatory bowel disease (IBD). However, factors and molecular signals sustaining TR1 cell regulatory activity still need to be identified in order to optimize the efficiency and to ensure the safety of these trials. We investigated the role of IL-10 signaling in mature TR1 cells in vivo. Double IL-10eGFP Foxp3mRFP reporter mice and transgenic mice with impairment in IL-10 receptor signaling were used to test the activity of TR1 cells in a murine IBD model, a model that resembles the trials performed in humans. The molecular signaling was elucidated in vitro. Finally, we used human TR1 cells, currently employed for cell therapy, to confirm our results. We found that murine TR1 cells expressed functional IL-10 receptor α. TR1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. TR1 cells required IL-10 receptor signaling in order to activate p38 MAP kinase, thereby sustaining IL-10 production, which ultimately mediated their suppressive activity. Finally, we confirmed these data using human TR1 cells. In conclusion TR1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that in order to optimize TR1 cell-based therapy, IL-10 receptor expression has to be taken into consideration.

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