scholarly journals SHP-2 and canonical PD-1: SHP-2 axis regulate myeloid cell differentiation, anti-tumor responses and innate immune memory

2022 ◽  
Author(s):  
Vassiliki Boussiotis ◽  
Anthos Christofides ◽  
Xanthi-Lida Katopodi ◽  
Carol Cao ◽  
Halil-Ibrahim Aksoylar ◽  
...  
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Antigen Processing ◽  
Innate Immune ◽  
Lineage Commitment ◽  
Immune Memory ◽  
Myeloid Differentiation ◽  
Gm Csf

Abstract PD-1 checkpoint inhibitor induces T cell inactivation by recruiting SHP-2. However, T cell-specific SHP-2-deficient mice do not have improved anti-tumor immunity. We generated mice with conditional targeting of the Ptpn11 gene (encoding for Shp-2) in T cells (Shp2f/fLckCre) or myeloid cells (Shp2f/fLysMCre), and found that Shp2f/fLysMCre mice had diminished tumor growth. As determined by RNA-seq, this was paralleled by the presence of inflammatory neutrophils and tumor-associated macrophages (TAMs) with molecular signatures of enhanced differentiation, phagocytosis and antigen-processing and presentation. SHP-2 deficient TAMs also had increased monocyte and dendritic cell (DC) specification transcription factors, chemokine and cytokine production, and expression of immunostimulatory molecules that promote T cell recruitment and activation. Monocytes from tumor-bearing Shp2f/fLysMCre mice suppressed tumor growth after transfer to naïve recipients indicating development of innate immune memory. In bone marrow myelocytes, GM-CSF, induced PD-1 expression, phosphorylation and interaction with SHP-2, the Src family kinase Lyn, and GM-CSF receptor beta chain, indicating that the PD-1:SHP-2 axis targets a key pathway of myelocyte differentiation. In contrast, SHP-2 deletion or antibody-mediated blockade of the PD-1:PD-L1 pathway enhanced phosphorylation of the transcription factors HOXA10 and IRF8 that regulate myeloid differentiation and monocytic/moDC lineage commitment, respectively. Thus, SHP-2 and the PD-1:SHP-2 axis pose a signaling restrain to myeloid differentiation and monocyte lineage commitment resulting in a myeloid landscape that suppresses anti-tumor immunity.

Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors

1994 ◽  
Vol 14 (2) ◽  
pp. 1153-1159
Author(s):  
C Y Wang ◽  
A G Bassuk ◽  
L H Boise ◽  
C B Thompson ◽  
R Bravo ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nuclear Protein ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Transcriptional Induction

The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene has been studied extensively as a model system of transcriptional induction during T-lymphocyte activation. The GM-CSF gene is not expressed in resting peripheral blood T cells but is rapidly induced at the transcriptional level following activation through the cell surface T-cell receptor. A highly conserved 19-bp element located immediately 5' of the human GM-CSF TATA box (bp -34 to -52), herein called purine box 1 (PB1), has been shown to bind a T-cell nuclear protein complex and to be required for transcriptional induction of the GM-CSF gene following T-cell activation. The PB1 sequence motif is highly conserved in both human and murine GM-CSF genes. In this report, we demonstrate that the PB1 element alone confers inducibility on a heterologous promoter following transfection into human Jurkat T cells. In addition, we identify a major PB1 nuclear protein-binding complex that is not present in resting peripheral blood T cells but is rapidly induced following T-cell activation. Sequence analysis revealed that PB1 is composed of adjacent binding sites for Ets and AP-1 transcription factors. In vitro mutagenesis experiments demonstrated that both the Ets and AP-1 sites are required for binding of the inducible PB1 nuclear protein complex and for the transcriptional activity of this element and the GM-CSF promoter in activated T cells. Using antibodies specific for different Ets and AP-1 family members, we demonstrate that the major inducible PB1-binding activity present in activated T-cell nuclear extracts is composed of the Elf-1, c-Fos, and JunB transcription factors. Taken together, these results suggest that cooperative interactions between specific Ets and AP-1 family members are important in regulating inducible gene expression following T-cell activation.

scholarly journals Transcription tipping points for T follicular helper cell and T-helper 1 cell fate commitment

2020 ◽  
Author(s):  
Amania A. Sheikh ◽  
Joanna R. Groom
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Inflammatory Responses ◽  
Immune Memory ◽  
Transcriptional Networks ◽  
T Helper ◽  
T Helper 1 ◽  
Extrinsic Factors ◽  
Tfh Cells ◽  
Follicular Helper

Abstract During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4+ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4+ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4+ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4+ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

Pak2 Regulates MDSC Development and Function

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 705-705
Author(s):  
Yi Zeng ◽  
Seongmin Hahn ◽  
Jessica Stokes ◽  
Emely Hoffman ◽  
Jonathan Chernoff ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Progenitor Cells ◽  
Lineage Commitment ◽  
T Cell Proliferation ◽  
Myeloid Lineage ◽  
Suppressive Function ◽  
Gm Csf ◽  
Group I

Abstract Myeloid derived suppressor cells (MDSCs) are a heterogeneous cell population at various stages of differentiation that can increase under various pathologic conditions such as cancer, infection or inflammation, displaying suppressive function. It is well recognized that MDSCs contribute to tumor evasion by suppressing cell-mediated immunity. Based on the differential expression of Ly6C and/or Ly6G in mice, MDSCs are characterized as granulocytic (CD11b+Ly6G+Ly6Clow) or monocytic MDSCs (CD11b+Ly6Glow/−Ly6Chi). These subsets induce T-cell hyporesponsiveness and can have various functions and distribution depending on their environment. Although much research has focused on the tumorigenic effects of MDSCs, studies on the regulation of their development during hematopoiesis remain limited. p21-activated kinases (Paks) are serine/threonine kinases that regulate diverse cellular activities including cytoskeletal remodeling, cell motility, proliferation, apoptosis and mitosis. Despite active research on pharmacological inhibition of group I Paks in treating solid tumors, few studies have examined the role of Paks in modulating normal hematopoiesis. Knowledge of the role of Pak2 in regulating long-term hematopoiesis and lineage commitment remains limited. Utilizing a conditional Pak2-KO murine model, we have previously demonstrated that Pak2 disruption in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and CD11b+Gr1+ cell expansion in mice. Compared to mice reconstituted with wild type (WT) bone marrow (BM), mice transplanted with Pak2-KO BM displayed a significantly higher percentage of granulocyte-monocyte progenitors (GMPs) in the BM and higher numbers of CD11b+Gr1+ cells in the spleen. In this study, we demonstrated that CD11b+Gr1high cells isolated from the spleens of mice with Pak2-KO BM displayed significantly greater suppressive function on T cell proliferation in vitro, consistent with MDSC phenotype. There was a near 2-fold increase in the numbers of both granulocytic and monocytic splenic MDSCs in mice reconstituted with Pak2-KO BM. At HSPC level, Pak2-KO BM yielded greater than 3-fold more colonies in response to GM-CSF but not G-CSF or M-CSF when compared to WT cells, indicating selective hypersensitivity to GM-CSF. In parallel experiments, Pak2-KO and WT BM C-kit+ cells that were enriched for hematopoietic progenitor cells (HPCs) were cultured in liquid culture in the presence of GM-CSF. Pak2-KO BM C-kit+ cells yielded greater than 2-fold higher numbers of CD11b+Gr1+ MDSCs that displayed potent suppression on CD8+ T cell proliferation. These data demonstrate that Pak2 disruption increases HPC sensitivity to GM-CSF signaling and drives lineage commitment toward granulocyte-monocyte lineage thus promoting MDSC development. In addition, we have also found that Pak2 deficient MDSCs are more proliferative and more resistant to apoptosis when compared to WT CD11b+Gr1+cells, thus contributing to expansion of this population in vivo. Loss of Pak2 decreases MDSC sensitivity to apoptosis through differential regulation of multiple pro- and anti-apoptotic gene expression. Furthermore, Pak2 disruption down regulates the expression of IRF8, a well-described myeloid transcription factor. Together, our data indicate that loss of Pak2 promotes HPC myeloid lineage commitment and CD11b+Gr1+ MDSC proliferation while suppressing apoptotic cell death in these cells. Further studies are ongoing to determine the interaction between Pak2 and IRF8. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dietary methionine restriction impairs anti-tumor immunity through gut microbiota

2021 ◽  
Author(s):  
Ming Li ◽  
Xiaojiang Xu ◽  
Qing Xu ◽  
Xin Xu ◽  
M Andrea Azcarate-Peril ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Immune System ◽  
T Cell ◽  
Gut Microbiota ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cancer Growth ◽  
Methionine Restriction

Dietary methionine restriction has been reported to repress cancer growth and improve therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the intact immune system is unknown. Here we report that methionine restriction exacerbates cancer growth and influences the outcomes of anti-tumor immunotherapy through gut microbiota and immune suppression in immunocompetent settings. Methionine restriction reduces T cell activation, increases tumor growth, and impairs response to anti-tumor immunotherapy. Mechanistically, methionine restriction alters composition of gut microbiota and reduces microbial production of hydrogen sulfide. Fecal transplantation from methionine-restricted tumor-free animals is sufficient to repress T cell activation and enhance tumor growth in tumor-bearing recipient mice. Conversely, dietary supplementation of a hydrogen sulfide donor or methionine stimulates anti-tumor immunity and suppresses tumor progression. Our findings reveal a vital role of gut microbiota in mediating methionine restriction-induced suppression of anti-tumor immunity and suggest that any possible anti-cancer benefits of methionine restriction require careful considerations of both the microbiota and the immune system.

scholarly journals Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3131-3148 ◽  
Author(s):  
M.K. Anderson ◽  
G. Hernandez-Hoyos ◽  
R.A. Diamond ◽  
E.V. Rothenberg
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
B Cell ◽  
Developmental Stages ◽  
Developmental Regulation ◽  
Hematopoietic Cells ◽  
Cell Lineage ◽  
Lineage Commitment ◽  
Lineage Specification ◽  
Ets Family

Ets family transcription factors control the expression of a large number of genes in hematopoietic cells. Here we show strikingly precise differential expression of a subset of these genes marking critical, early stages of mouse lymphocyte cell-type specification. Initially, the Ets family member factor Erg was identified during an arrayed cDNA library screen for genes encoding transcription factors expressed specifically during T cell lineage commitment. Multiparameter fluorescence-activated cell sorting for over a dozen cell surface markers was used to isolate 18 distinct primary-cell populations representing discrete T cell and B cell developmental stages, pluripotent lymphoid precursors, immature NK-like cells and myeloid hematopoietic cells. These populations were monitored for mRNA expression of the Erg, Ets-1, Ets-2, Fli-1, Tel, Elf-1, GABPalpha, PU.1 and Spi-B genes. The earliest stages in T cell differentiation show particularly dynamic Ets family gene regulation, with sharp transitions in expression correlating with specification and commitment events. Ets, Spi-B and PU.1 are expressed in these stages but not by later T-lineage cells. Erg is induced during T-lineage specification and then silenced permanently, after commitment, at the beta-selection checkpoint. Spi-B is transiently upregulated during commitment and then silenced at the same stage as Erg. T-lineage commitment itself is marked by repression of PU.1, a factor that regulates B-cell and myeloid genes. These results show that the set of Ets factors mobilized during T-lineage specification and commitment is different from the set that maintains T cell gene expression during thymocyte repertoire selection and in all classes of mature T cells.

scholarly journals β-glucan-induced innate immune memory distinctively affects macrophage activation in response to differential environmental cues

2021 ◽  
Author(s):  
Alícia C. Piffer ◽  
Giorgio Camilli ◽  
Mathieu Bohm ◽  
Rachel Lavenir ◽  
Jessica Quintin
Keyword(s):  
Local Environment ◽  
Innate Immune ◽  
Immune Memory ◽  
Gm Csf ◽  
Different Types ◽  
And Function ◽  
Previous Encounter ◽  
Functional Phenotype

AbstractAdvances in the field of immunological memory demonstrate that innate immune cells can recall a previous encounter – the innate immune memory. In vitro, exposure of human primary monocytes to the fungal ²-glucan enhances their pro-inflammatory responsiveness towards several pathogens. During infection, circulating monocytes infiltrate tissues where, following conditioning by local environment, they differentiate and polarise into different types of macrophages. Hence in vivo interaction of β-glucan with innate cells would occur in a complex environment. Understanding the potential of β-glucan to induce innate immune memory in complex physiological environments is crucial for future translational research.Recapitulating different physiological conditions in vitro we found that β-glucan imprinting does not always enhance responsiveness and function of macrophages but can also reduce it. In this study, we show that upon both GM-CSF- and M-CSF-mediated polarisation, imprinting by β-glucan leads to less differentiated macrophages with a convergent functional phenotype. Altogether, these observations provide insightful and crucial knowledge that will help apprehending the in vivo high potential of β-glucan-induced innate memory in different pathological contexts.

scholarly journals Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells

2021 ◽  
Vol 218 (8) ◽  
Author(s):  
Hiroyuki Hosokawa ◽  
Maria Koizumi ◽  
Kaori Masuhara ◽  
Maile Romero-Wolf ◽  
Tomoaki Tanaka ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
T Cell ◽  
Cell Line ◽  
Functional Site ◽  
Lineage Commitment ◽  
Factor Binding ◽  
Ets Family ◽  
Intron 2

PU.1 (encoded by Spi1), an ETS-family transcription factor with many hematopoietic roles, is highly expressed in the earliest intrathymic T cell progenitors but must be down-regulated during T lineage commitment. The transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression, but the basis of the timing was unknown. We show that increasing Runx1 and/or GATA3 down-regulates Spi1 expression in pro–T cells, while deletion of these factors after Spi1 down-regulation reactivates its expression. Leveraging the stage specificities of repression and transcription factor binding revealed an unconventional but functional site in Spi1 intron 2. Acute Cas9-mediated deletion or disruption of the Runx and GATA motifs in this element reactivates silenced Spi1 expression in a pro–T cell line, substantially more than disruption of other candidate elements, and counteracts the repression of Spi1 in primary pro–T cells during commitment. Thus, Runx1 and GATA3 work stage specifically through an intronic silencing element in mouse Spi1 to control strength and maintenance of Spi1 repression during T lineage commitment.

scholarly journals GM-CSF mediates immune evasion via upregulation of PD-L1 expression in extranodal natural killer/T cell lymphoma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Qi-xiang Rong ◽  
Fang Wang ◽  
Zhi-xing Guo ◽  
Yi Hu ◽  
Sai-nan An ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Disease Progression ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Tissue Samples ◽  
Natural Killer T Cell ◽  
Gm Csf ◽  
Killer T Cell

Abstract Background Granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine that is used as an immunopotentiator for anti-tumor therapies in recent years. We found that some of the extranodal natural killer/T cell lymphoma (ENKTL) patients with the treatment of hGM-CSF rapidly experienced disease progression, but the underlying mechanisms remain to be elucidated. Here, we aimed to explore the mechanisms of disease progression triggered by GM-CSF in ENKTL. Methods The mouse models bearing EL4 cell tumors were established to investigate the effects of GM-CSF on tumor growth and T cell infiltration and function. Human ENKTL cell lines including NK-YS, SNK-6, and SNT-8 were used to explore the expression of programmed death-ligand 1 (PD-L1) induced by GM-CSF. To further study the mechanisms of disease progression of ENKTL in detail, the mutations and gene expression profile were examined by next-generation sequence (NGS) in the ENKTL patient’s tumor tissue samples. Results The mouse-bearing EL4 cell tumor exhibited a faster tumor growth rate and poorer survival in the treatment with GM-CSF alone than in treatment with IgG or the combination of GM-CSF and PD-1 antibody. The PD-L1 expression at mRNA and protein levels was significantly increased in ENKTL cells treated with GM-CSF. STAT5A high-frequency mutation including p.R131G, p.D475N, p.F706fs, p.V707E, and p.S710F was found in 12 ENKTL cases with baseline tissue samples. Importantly, STAT5A-V706fs mutation tumor cells exhibited increased activation of STAT5A pathway and PD-L1 overexpression in the presence of GM-CSF. Conclusions These findings demonstrate that GM-CSF potentially triggers the loss of tumor immune surveillance in ENKTL patients and promotes disease progression, which is associated with STAT5 mutations and JAK2 hyperphosphorylation and then upregulates the expression of PD-L1. These may provide new concepts for GM-CSF application and new strategies for the treatment of ENKTL.

scholarly journals The Role of TAL1 in Hematopoiesis and Leukemogenesis

Acta Naturae ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 15-23 ◽  
Author(s):  
E. R. Vagapova ◽  
P. V. Spirin ◽  
T. D. Lebedev ◽  
V. S. Prassolov
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Blood Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Formation ◽  
Myeloid Differentiation ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia

TAL1 (SCL/TAL1, T-cell acute leukemia protein 1) is a transcription factor that is involved in the process of hematopoiesis and leukemogenesis. It participates in blood cell formation, forms mesoderm in early embryogenesis, and regulates hematopoiesis in adult organisms. TAL1 is essential in maintaining the multipotency of hematopoietic stem cells (HSC) and keeping them in quiescence (stage G0). TAL1 forms complexes with various transcription factors, regulating hematopoiesis (E2A/HEB, GATA1-3, LMO1-2, Ldb1, ETO2, RUNX1, ERG, FLI1). In these complexes, TAL1 regulates normal myeloid differentiation, controls the proliferation of erythroid progenitors, and determines the choice of the direction of HSC differentiation. The transcription factors TAL1, E2A, GATA1 (or GATA2), LMO2, and Ldb1 are the major components of the SCL complex. In addition to normal hematopoiesis, this complex may also be involved in the process of blood cell malignant transformation. Upregulation of C-KIT expression is one of the main roles played by the SCL complex. Today, TAL1 and its partners are considered promising therapeutic targets in the treatment of T-cell acute lymphoblastic leukemia.

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