The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases

Roncarolo, Maria Grazia; Gregori, Silvia; Bacchetta, Rosa; Battaglia, Manuela; Gagliani, Nicola

doi:10.1016/j.immuni.2018.12.001

Cited by 236 publications

(214 citation statements)

References 146 publications

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“…Besides its role in regulating cytotoxic activity of CD4 + T-cells, the importance of EOMES in the generation of T R 1 T-cells was recently shown (7, 8). T R 1 T-cells do not constitutively express FOXP3, produce the immunosuppressive cytokine IL-10, express co-inhibitory receptors such as PD-1, and are able to suppress the function of effector immune cells (10). The expression of IL-10 and other cytokines and their receptors, in combination with increased expression levels of inhibitory receptors are shared features of CD4 + EOMES + T-cells in B-NHL and T R 1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Despite abundant data characterizing CD4 + T-cells and their subsets in B-cell Non-Hodgkin lymphoma (B-NHL) (1), and in particularly chronic lymphocytic leukemia (CLL) (2-6), their role in disease development and progression is poorly understood. Besides well-known T helper (Th) cell subsets (5), interleukin (IL-)10 producing, FOXP3 - conventional CD4 + T-cells, named type 1 regulatory (T R 1) cells, are gaining attention in mouse models as well as patients harboring chronic inflammatory conditions such as inflammatory bowel disease (7-10). T R 1 cells were initially described as IL-10-induced cells that produce IL-10 and IFNγ and harbor cytotoxic activity, but also express several co-inhibitory receptors such as programmed cell death protein-1 (PD-1).…”

Section: Introductionmentioning

confidence: 99%

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EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

Roessner

Lupar

et al. 2020

Preprint

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41The transcription factor Eomesodermin (EOMES) promotes IL-10 production of CD4 + T-cells, which has 42 been linked to immunosuppressive and cytotoxic activities. We detected EOMES-expressing CD4 + T-43 cells in lymph node samples of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell 44 lymphoma. This was in line with an observed expansion of EOMES-positive CD4 + T-cells in leukemic Eµ-45 TCL1 mice, a well-established model of CLL, and upon adoptive transfer of TCL1 leukemia in mice. 46Transcriptome and flow cytometry analyses revealed that EOMES does not only drive the transcription 47 of IL-10, but rather controls a unique differentiation program in CD4 + T-cells. Moreover, EOMES was 48 necessary for the accumulation of a specific CD4 + T-cell subset that expresses IFNγ and IL-10, as well 49 as inhibitory receptors, like PD-1 and LAG3. T-cell transfer studies in leukopenic Rag2 -/mice showed 50 that EOMES-deficient CD4 + T-cells were inferior in controlling TCL1 leukemia development compared 51 to wildtype T-cells, even though expansion of Eomes -/-CD4 + T-cells was observed. We further showed 52 that control of TCL1 leukemia was driven by IL-10 receptor-mediated signals, as Il10rb-deficient CD4 + 53 T-cells showed impaired anti-leukemia activity. Altogether, our data suggest that IL-10 producing PD-54

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

Roessner

Lupar

et al. 2020

Preprint

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“…Co-expression analysis of the expression levels of immune cells obtained in this study showed that the correlation between T cells regulatory (Tregs) [10][11][12][13]and Neutrophils [14][15][16][17] was the strongest, with a coe cient of 0.78, and the two cells with the weakest correlation were Macrophages [18][19] and T cells follicular helper [20][21], the correlation coe cient is -0.59 (Figure 3). After obtaining the matrix of immune cells, we wondered whether these immune cells could distinguish between the normal group and the tumor group.…”

Section: Co-expression Analysis Between Immune Cellsmentioning

confidence: 77%

Immune Infiltrating Cells in Cholangiocarcinoma May Become Clinical Diagnostic Markers: Based on Bioinformatics Analysis.

Zhang

Chen

et al. 2020

Preprint

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Background: intrahepatic cholangiocarcinoma (ICC) is a malignant tumor originating from the secondary bile duct and its branch epithelium. Among primary liver tumors, the incidence of ICC is second only to hepatocellular carcinoma. tumor microenvironment can regulate the occurrence and development of tumors. This study is dedicated to finding more markers that can diagnose ICC by finding the differential tumor microenvironment cells between ICC and normal tissues. Methods: We wanted to study the infiltration of immune cells between the cholangiocarcinoma of the same patient and its paired non-tumor tissues, to explore the difference of immune cells in the tumor microenvironment and adjacent non-tumor tissues in the same organism. So, we searched the relevant data of patients with ICC from the GEO database and found that the GSE45001 data set meets our research needs. CIBERSORT database is used to calculate immune cell composition. Finally, perform visual analysis and data statistics to find out the differentially expressed immune cells.Results: we found that the expression levels of Dendritic cells activated, Macrophages M2 and T cells regulatory (Tregs) in ICC were higher than normal tissues and the expression levels of Macrophages M1, Monocytes and T cells follicular helper in ICC were lower than normal tissues. Conclusion: These 6 types of immune cells are expected to become molecular markers for clinical diagnosis of ICC.

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“…This transcriptomic signature seems to be disease-specific, although similarities with other pathogenic CD4 T cells involved in several autoimmune disorders were observed. Indeed, in autoimmune disorders, distinct pathogenic CD4 T cell molecular signatures have been reported, including a TFH and TPH signature 5,6,9,18,22,24,25 , a TH10 and Tr1/Treg 23,48,49 (regulatory T cell) signature, and a TH17-like signature 16,19,20,38,50 . Here, we have shown that SLA-specific CD4 T cells had a transcriptomic signature close to the TPH signature 22,24,25 (IFNG, IL21, MAF, CD200, ICOS, CTLA4, ITM2A, TIGIT and SLAMF6).…”

Section: Discussionmentioning

confidence: 99%

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis

Renaud

Cervera-Marzal

Gil

et al. 2020

Preprint

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Background & Aims: In most autoimmune disorders, crosstalk of B cells and CD4 T cells resultsin the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-Soluble Liver Antigen (SLA or SepSecs) autoantibodies is associated with significantly reduced overall survival, but the associated autoreactive CD4 T cells have not been characterized yet.Here we isolated and deeply characterized SLA-specific CD4 T cells in AIH patients. Methods: We used brief ex vivo restimulation with overlapping SLA-derived peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNAseq) to characterize their transcriptome and TCR repertoire in n=5 AIH patients. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing, to identify their phenotypic niche. We further characterized disease-associated peripheral blood T cells by high content flow cytometry in an additional cohort of n=46 AIH patients and n=18 non-alcoholic steatohepatitis (NASH) controls. Results: Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1 + CXCR5 -CCR6 -CD27 + phenotype. ScRNA-seq revealed their pro-inflammatory/B-Helper profile ( IL21, IFNG, TIGIT, CTLA4, NR3C1, CD109, KLRB1 and CLEC2D). Autoreactive TCR clonotypes were restricted to the memory PD-1 + CXCR5 -CD4 T cells. This subset was significantly increased in the blood of AIH patients and supportedB cell differentiation through IL-21. Finally, we identified a specific phenotype (PD-1 + CD38 + CD27 + CD127 -CXCR5 -) of CD4 T cells linked to disease activity and IgG response during AIH. Conclusions: This work provides for the first time a deep characterization of rare circulating autoreactive CD4 T cells and the identification of their peripheral reservoir in AIH. We also propose a generic phenotype of pathogenic CD4 T cells related to AIH disease activity.

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The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases

Cited by 236 publications

References 146 publications

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

Immune Infiltrating Cells in Cholangiocarcinoma May Become Clinical Diagnostic Markers: Based on Bioinformatics Analysis.

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis

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The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases

Cited by 236 publications

References 146 publications

EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

Immune Infiltrating Cells in Cholangiocarcinoma May Become Clinical Diagnostic Markers: Based on Bioinformatics Analysis.

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis

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Product

Resources

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EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma