scholarly journals The BTB-ZF Family of Transcription Factors: Key Regulators of Lineage Commitment and Effector Function Development in the Immune System

2011 ◽  
Vol 187 (6) ◽  
pp. 2841-2847 ◽  
Author(s):  
Aimee M. Beaulieu ◽  
Derek B. Sant'Angelo
Keyword(s):  
Transcription Factors ◽  
Immune System ◽  
Effector Function ◽  
Lineage Commitment

scholarly journals OP0307 A NOVEL TARGETED APPROACH TO ACHIEVE IMMUNE SYSTEM RESET: CD45-TARGETED ANTIBODY DRUG CONJUGATES AMELIORATE DISEASE IN PRECLINICAL AUTOIMMUNE DISEASE MODELS AND ENABLE AUTO-HSCT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 190-191
Author(s):  
G. Gillard ◽  
J. Proctor ◽  
S. Hyzy ◽  
O. Mikse ◽  
T. Lamothe ◽  
...  
Keyword(s):  
Single Dose ◽  
Immune System ◽  
Autoimmune Disease ◽  
Disease Onset ◽  
Effector Function ◽  
Disease Models ◽  
Cell Transplant ◽  
Site Specific ◽  
Donor Chimerism ◽  
Multiple Sclerosis Patients

Background:Resetting the immune system through autologous hematopoietic stem cell transplant (autoHSCT) is a highly effective treatment in selected patients with autoimmune diseases. AutoHSCT can induce long-term remission with 80% progression free survival in multiple sclerosis patients (Muraro 2017, Burt 2019). Use of autoHSCT in scleroderma patients has achieved superior outcomes in two randomized studies compared to standard of care (Tyndall 2014, Sullivan 2018). These impressive results are achieved by a combination of the eradication of autoreactive immune effector cells and re-establishment of self-tolerance, i.e., immune system reset. However, only a small fraction of eligible patients undergo autoHSCT, largely due to toxicity associated with current conditioning protocols.Objectives:As part of our goal to enable more patients to benefit from immune system reset, we have generated novel anti-human CD45 ADCs that cross react with nonhuman primates (NHP) and an anti-mouse CD45 ADC to model the approach in mouse models of AID.Methods:The human-targeted CD45-ADC is an affinity-matured mAb that targets an epitope present on all human CD45 isoforms, is cross-reactive with NHP CD45, and is conjugated to a payload that efficiently kills both quiescent and cycling cells. This ADC is engineered to eliminate Fc-mediated effector function, enable site-specific conjugation of linker/payload, and enable rapid clearance. This ADC was evaluated in vitro and in vivo in hNSG and NHPs. The murine tool ADC specifically targets the CD45.2 isoform of mouse CD45, and is also engineered to eliminate effector function, allow for site-specific conjugation of linker payload, and be rapidly cleared. The payload for this murine tool ADC is potent and preferentially kills dividing cells. This ADC was tested for the ability to enable immune reset and ameliorate autoimmune disease in multiple disease models.Results:The anti-human CD45-ADC showed efficient killing of human HSCs and human and cyno PBMC, including CD3+cells from healthy donors and patients with MS. In hNSG, single doses of the CD45-ADC were well-tolerated and led to substantial depletion of human cells. In NHPs, single doses of CD45-ADC were well tolerated and depleted both peripheral lymphocytes and HSCs. Administration of a single dose of anti-human CD45-ADC to hNSGs with sclerodermatous xenoGVHD resulted in depletion of human T cells and resolution of symptoms. A single-dose of the anti-mouse CD45-ADC enabled full myeloablation and complete durable donor chimerism with congenic HSCT at 16 weeks. In a murine immunization model of MS, MOG-induced EAE, a single dose of the CD45-ADC followed by congenic HSCT prior to disease onset enabled full donor chimerism, significantly delayed disease onset and reduced disease severity. We are generating additional data in an adoptive transfer model of EAE to confirm and extend these results. In a murine model of arthritis, therapeutic treatment with a single dose of the CD45-ADC followed by congenic HSCT enabled complete donor chimerism and halted disease progression, comparable to with the effects of an anti-TNFα antibody. The ADC is being further evaluated in a model of type 1 diabetes and those data will be presented. These data demonstrate that CD45-ADC conditioning followed by congenic HSCT is sufficient for full myeloablation and immune reset.Conclusion:These results demonstrate that targeted immune depletion with a single dose of CD45-ADC can enable auto-HSCT and immune reset in multiple AID indications without toxic side effects. Targeted conditioning with CD45-ADC may represent a better tolerated approach for removing disease-causing cells as part of immune reset through auto-HSCT and enable more patients to benefit.Disclosure of Interests:Geoffrey Gillard Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Jennifer Proctor Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Sharon Hyzy Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Oliver Mikse Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Tahirih Lamothe Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Sean McDonough Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Nicholas Clark Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Rahul Palchaudhuri Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Anjali Bhat Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Melissa Brooks Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Ganapathy Sarma Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Prashant Bhattarai Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Pranoti Sawant Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Brad Pearse Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Charlotte McDonagh Shareholder of: Magenta Therapeutics, Employee of: Magenta Therapeutics, Tony Boitano Shareholder of: Magenta, Employee of: Magenta, Michael Cooke Shareholder of: Magenta, Employee of: Magenta

scholarly journals Lineage commitment in the immune system: the T helper lymphocyte grows up

2000 ◽  
Vol 14 (14) ◽  
pp. 1693-1711 ◽  
Author(s):  
Laurie H. Glimcher ◽  
Kenneth M. Murphy
Keyword(s):  
Immune System ◽  
Lineage Commitment ◽  
T Helper ◽  
Helper Lymphocyte ◽  
T Helper Lymphocyte

scholarly journals Highly Specialized Role of Forkhead Box O Transcription Factors in the Immune System

2011 ◽  
Vol 14 (4) ◽  
pp. 663-674 ◽  
Author(s):  
Anne S. Dejean ◽  
Stephen M. Hedrick ◽  
Yann M. Kerdiles
Keyword(s):  
Transcription Factors ◽  
Immune System ◽  
Forkhead Box

Symmetry of effector function in the immune system network

1983 ◽  
Vol 20 (8) ◽  
pp. 865-870 ◽  
Author(s):  
Anwyl Cooper-Willis ◽  
Geoffrey W. Hoffmann
Keyword(s):  
Immune System ◽  
Effector Function

scholarly journals T Helper Lymphocyte Subsets and Plasticity in Autoimmunity and Cancer: An Overview

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Ekaterina A. Ivanova ◽  
Alexander N. Orekhov
Keyword(s):  
Transcription Factors ◽  
Immune System ◽  
Autoimmune Diseases ◽  
T Lymphocyte ◽  
Lymphocyte Subsets ◽  
T Helper ◽  
T Lymphocyte Subsets ◽  
Adequate Response ◽  
T Helper Lymphocyte ◽  
Th1 And Th2

In response to cytokine signalling and other factors, CD4-positive T lymphocytes differentiate into distinct populations that are characterized by the production of certain cytokines and are controlled by different master transcription factors. The spectrum of such populations, which was initially limited to Th1 and Th2 subsets, is currently broadened to include Th17 and Treg subsets, as well as a number of less studied subtypes, such as Tfh, Th9, and Th22. Although these subsets appear to be relatively stable, certain plasticity exists that allows for transition between the subsets and formation of hybrid transition forms. This provides the immune system flexibility needed for adequate response to pathogens but, at the same time, can play a role in the pathogenic processes in cases of deregulation. In this review, we will discuss the properties of T lymphocyte subsets and their plasticity, as well as its implications for cancer and autoimmune diseases.

Molecular Background of BCP-ALL Cases with an Early Switch to Monocytic Lineage

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3562-3562
Author(s):  
Karel Fišer ◽  
Lucie Slámová ◽  
Alena Dobiášová ◽  
Júlia Starková ◽  
Eva Froňková ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factors ◽  
B Cell ◽  
Differentially Expressed ◽  
Lineage Commitment ◽  
Altered Expression ◽  
B Lineage ◽  
And Control ◽  
Monocytic Lineage

Abstract We identified a subset of BCP-ALL with switch towards the monocytic lineage within the first month of treatment (swALL)[Slámová et al Leukemia 2014]. During the switch cells gradually lose CD19 and CD34 expression and acquire CD33 and CD14 positivity. We proved clonal relatedness of switched monocytic blasts with the diagnostic leukemic cells based on identical Ig-TCR rearrangements. SwALL cases are not associated with MLL or BCR/ABL1 aberrancies and lack any known genetic markers of lineage ambiguity (detected by FISH or MLPA). We analyzed transcriptomes of swALL samples at diagnosis (n=4) and at d8 (n=4) where the immunophenotypic switching was already apparent as well as control BCP-ALL (n=4). RNA was isolated form either FACS sorted cells or whole BM when blasts constituted >80% of cells. For RNA-Seq we used Illumina HiSeq 2000 paired-end or single end sequencing. Raw sequencing data were analyzed using adapted protocol from Anders at al [Anders et al Nature Protocols 2013] and custom scripts. For methylome analysis we used Enhanced Reduced Representation Bisulfite Sequencing (ERRBS)[Akalin et al PLoS Genetics 2012]. ERRBS quantitatively measures DNA methylation at ~3M CpGs genome-wide. Samples from swALL at diagnosis (n=7) and at d8 (n=4) and control BCP-ALL (n=4) were processed. Analysis was performed according to [Akalin et al Genome Biology 2012] and followed with custom analysis in R statistical language. Comparison (generalized exact binomial test) of transcriptomes of B-lineage blasts from diagnosis between swALLs and control BCP-ALLs revealed a number of differentially expressed genes. Among 300 most significantly differentially expressed were KLF4, CEBPD, CLEC12A and CLEC12B (upregulated in swALL) and ANXA5, VPREB1, CD9 and IGHG3 (downregulated in swALL). Hierarchical clustering separated not only swALL and control BCP-ALL, but also swALL cells before and during the monocytic switch. Changes in gene expression during lineage switch included downregulation of ITGA6, Id2, EBF1, CD19, CD34, FLT3, MYB, CD79a, BCR, PAX5, GATA3 and TCF3 genes and upregulation of S100A10, AIF1, CD14, CD33, LGALS1, RNF130 and MNDA. When comparing all three cell types (swALL B cell and monocytic blasts and control BCP-ALL blasts) we concentrated on 1) immunophenotype switch markers and 2) lineage related transcription factors (TF): 1) Both markers typical for B cell blasts (CD19, CD34) decreased during the switch. However while CD19 was expressed in swALL at diagnosis at same levels as in control BCP-ALL, CD34 was overexpressed in swALL compared to BCP-ALL at diagnosis. Both monocytic markers (CD33, CD14) increased their expression during the switch. CD14 showed no difference between swALL and control BCP-ALL at diagnosis. However CD33 was interestingly upregulated in swALL already at diagnosis and continued to rise during the switch. SwALL had therefore deregulated expression of lineage commitment markers already at diagnosis favoring stemness marker CD34 and myeloid marker CD33. 2) B lineage commitment related TFs (EBF1, TCF3, PAX5) were expressed in B lineage blasts in both swALL and control BCP-ALL. However they were all downregulated during the switch. On the other hand myeloid lineage related transcription factor CEBPA is overexpressed in diagnostic B lineage blasts in swALL compared to control BCP-ALL cases. Similarly CEBPD is overexpressed in swALL and its expression further rises during the switch. Other hematopoietic TFs upregulated in swALL cases include KLF4, NANOG and GATA3. To confirm some of the epigenetic markers of swALL cases (demethylation of CEBPA promoter) and to widen epigenetic screening we used ERRBS. While some of the upregulated genes had expectedly hypomethylated promoters in swALL (CEBPA, GATA3) other genes (TCF3, PAX5) had demethylated promoters in all cases. While the whole DNA methylation picture is still a challenge to draw both omics method could clearly separate swALL cases from control BCP-ALL using principal component analysis. In summary we show that immunophenotypic shift is associated with gene expression changes of surface markers, lineage specific transcription factors and other genes. Some of the genes have altered expression already at diagnosis. Expression of some key lineage genes is differentially regulated by DNA methylation. Supported by: GAUK 914613, GAČR P301/10/1877, UNCE 204012, IGA NT13462-4 Disclosures No relevant conflicts of interest to declare.

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 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.

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