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The role of ZNF74 in the generation and maintenance of immunological memory

English title The role of ZNF74 in the generation and maintenance of immunological memory
Applicant Recher Mike
Number 192652
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.04.2020 - 31.03.2024
Approved amount 761'492.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Clinical Immunology and Immunopathology

Keywords (9)

KZFP; Memory; B cells; T cells; KRAB zinc finger protein; Interferon; ZNF74; Primary Immunodeficiency; Immunodeficiency

Lay Summary (German)

Lead
Das immunologische Gedächtnis ist dafür verantwortlich, dass das menschliche Immunsystem bei wiederholtem Kontakt mit dem selben Pathogen (z.B. Virus) schneller und stärker reagiert, was in der Regel mit milderem Krankheitsverlauf assoziiert ist. Proteine, welche die Differenzierung und die Langlebigkeit von Gedächtnis T Lymphozyten (T Zellen) ermöglichen, sind nur teilweise bekannt. Dieses Forschungsprojekt möchte hierzu einen Beitrag leisten.
Lay summary
In einem Patienten mit ausgeprägtem Mangel an Gedächtnis T Zellen und dazu passenden wiederholten Herpes Zoster Virus Reaktivierungen konnte eine assoziierte, seltene, homozygote Mutation in einem Zinkfinger Transkriptionsfaktor, ZNF74, gefunden werden. Der Transkriptionsfaktor gehört zur Familie der KRAB Zinkfinger Proteine, welche via KAP-1 verschiedene Gene, aber auch endogene Retroviren über Histon-Methylierung negativ regulieren (reprimieren). Die Mutation verändert ZNF74 so, dass der Transkriptionsfaktor nicht in den üblichen Wirkungsort, den Zellkern gelangen kann.

Ziel dieses Projektes ist es, ausgehend von Immunzellen des Patienten vs. gesunden Kontroll-Personen sowie Immunzellen mit experimentell herbeigeführtem ZNF74 Mangel oder Ueberschuss, Proteine zu finden, welche in ihrer Expression durch ZNF74 kontrolliert werden. Dabei interessieren v.a. ZNF74 abhängige Eiweisse, welche die Entstehung oder das Ueberleben von Gedächtnis T Lymphozyten steuern.
Dabei wird methodisch die Genexpression aber auch der Metabolismus von ZNF74 kompetenten vs. defizienten T Lymphozyten verglichen. Die ZNF74 abhängige Histon-Methylierung wird Genom-weit charakterisiert.

Die Resultate dieses Forschungsprojektes können dazu beitragen, die Funktion von spezifischen KRAB Zinkfinger Transkriptionsfaktoren besser zu charakterisieren. Zudem kann ein Beitrag geleistet werden, die Entstehung von immunologischem T Zell Gedächtnis molekular besser zu verstehen.
Mehr klinisch orientiert kann durch dieses Forschungsprojekt die genetisch determinierte immunologische Erkrankung eines oder mehrerer Patienten mit ZNF74 Defizienz detailliert beschrieben, molekular charakterisiert und nach Möglichkeit mittels zielgerichteter medikamentöser Immunmodulation therapiert werden.





Direct link to Lay Summary Last update: 31.03.2020

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Associated projects

Number Title Start Funding scheme
181038 Immune-dysregulation and autoimmunity in primary immunodeficiency 01.01.2019 SNSF Professorships

Abstract

Background and Rationale:Adaptive immune cell (T and B cell) memory is ensuring human health despite constant encounter with pathogens. T cell memory differentiation is also essentially linked to potent immune surveillance of tumors and required for immune control of persistence prone pathogens. Proteins driving adaptive immune cell memory differentiation and/or maintenance with non-redundant roles in humans (‘in natura’) have only been identified in part. Primary immunodeficiencies (PID) are genetically determined human diseases presenting with susceptibility to infection, autoimmunity and impaired adaptive immune cell memory. Within a prospective cohort of patients with PID initiated by the applicant, we have identified patients with a unique PID characterized by specifically reduced adaptive memory T and B cells due to a homozygous truncating mutation in primate-specific KRAB zinc finger protein (KZFP) ZNF74. While the KZFP family has been shown to execute non-redundant roles in adaptive immune cells by influencing the T and B cell intrinsic epigenetic landscape, no specific KZFP family member has been linked to adaptive immune cell memory formation in humans.Overall Objectives:The overall objective of the proposal is to define the molecular role of ZNF74 in driving human T cell memory formation and/or maintenance, to characterize modulation of ZNF74 expression during T cell activation and function, and to identify druggable targets to deliberately dysregulate ZNF74 dependent adaptive immune cell memory.Specific Aims:The overall objectives will be experimentally assessed using the following specific aims:Specific aim (i): Identification of genes regulated by ZNF74 in human T cellsSpecific aim (ii): Characterization of the modulation of ZNF74 expression during T cell activationSpecific aim (iii): Analysis of the role of ZNF74 in memory human T cell differentiation and/or maintenanceSpecific aim (iv): Development of targeted strategies to alter ZNF4-associated T cell differentiation and/or maintenance in vitro and in vivoExpected Results:We expect, based on our preliminary experiments and concentrating on T cells, to characterize ZNF74 incompetence as a novel cause of human PID due to its essential non-redundant function to orchestrate adaptive immune cell memory formation in vitro and in vivo. ZNF74 dependent phenotypic, functional and epigenetic adaptations during human T cell activation and memory differentiation will be experimentally assessed. In addition, we might identify druggable targets dysregulated in human T cells associated with ZNF74 incompetence to subsequently concertedly facilitate ZNF74-driven adaptive immune memory formation in therapeutic or prophylactic immune therapy.Impact:From a basic immunology standpoint, characterization of non-redundant functions of ZNF74 might offer novel evidence how KZFP epigenetically regulate adaptive immunity. Translationally, the gain of knowledge from the proposed experiments may potentially accelerate the development of novel, ZNF74-targeted drugs to improve immune-mediated elimination of malignancy, to accelerate elimination of chronic virus infections and augment immune function in patients with immunodeficiency.
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