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Divergent Roles of CD4+ T Cells in H...

Bailey, Jacob T.,

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Divergent Roles of CD4+ T Cells in Humoral and Cellular Immune Responses to HBV /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Divergent Roles of CD4+ T Cells in Humoral and Cellular Immune Responses to HBV // Jacob T Bailey.
Author:	Bailey, Jacob T.,
Description:	1 electronic resource (181 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-10, Section: B.
Contained By:	Dissertations Abstracts International85-10B.
Subject:	Immunology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31146523
ISBN:	9798382200583

Divergent Roles of CD4+ T Cells in Humoral and Cellular Immune Responses to HBV /
Bailey, Jacob T.,

Divergent Roles of CD4+ T Cells in Humoral and Cellular Immune Responses to HBV /Jacob T Bailey. - 1 electronic resource (181 pages)

Source: Dissertations Abstracts International, Volume: 85-10, Section: B.

Hepatitis B virus (HBV) infection is a leading cause of viral hepatitis despite the availability of a safe and effective preventative vaccine. A major unresolved question concerning HBV is why the immune system tolerates infection. The "stealth" nature of the virus largely evades the innate immune response, and the adaptive immune response sometimes becomes dysfunctional, leading to viral persistence manifesting as chronic HBV infection (CHB). CHB is a lifelong morbidity, and disease intervention is ineffective at achieving a complete cure due to the stability of the transcriptional template known as cccDNA. The immune system is a favorable target for theoretical HBV intervention because of the connection between viral control and the magnitude of the initial immune response to HBV. Modern approaches for HBV immunotherapy favor immune checkpoint inhibition (ICI) and therapeutic vaccination strategies. To achieve this vision, I aimed to understand the role of the CD4+ T cell in its ability to regulate both humoral and cellular immune responses to HBV.The CD4+ T cell is the master regulator of an immune response; it permits full activation of the innate and adaptive arms while simultaneously restraining them to prevent excessive inflammation through processes known as T cell help. Because of its potent immunomodulatory capacity, the CD4+ T cell is expected to be a key determinant in virological outcomes following HBV infection. Using a mouse model of HBV replication, I evaluated the contribution of CD4+ T cells in HBV establishment. It became clear that HBsAg seroconversion, part of the functional cure for HBV, depended on CD4+ T cell help. Notably, HBsAg persisted following the repopulation of the CD4+ T cell compartment, and persistence was reversible upon splenocyte transfer. These findings imply that CD4+ T cell dysfunction might be a driving force behind HBV persistence.During my investigation of the CD4+ T cell's response to HBV infection, the CD40-CD40L axis was identified as a critical determinant of HBsAg seroconversion. This observation implored us to investigate the therapeutic potential of the CD40 signaling pathway in HBV control. Unexpectedly, activation of the CD40 signaling pathway via agonistic α-CD40 led to HBV control in a CD8+ T cell-dependent manner. This effect was amplified when administered to mice devoid of CD4+ T cells and suggests that CD4+ T cells function to restrict HBV-specific CD8+ T cells in this particular context.In this work, I aimed to delineate CD4+ T cell responses to HBV infection. We discovered divergent, context-dependent roles of the CD4+ T cell response, both productive and otherwise. The key takeaways from the studies presented within this dissertation are that 1. T cell help in HBV is productive in facilitating HBsAg seroconversion; 2. CD4+ T cells exhibit a tendency to minimize inflammation, particularly in the liver; and 3. CD40 represents a feasible target for inducing an HBV-resolving CD8+ T cell response.

English

ISBN: 9798382200583Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Immunization

Divergent Roles of CD4+ T Cells in Humoral and Cellular Immune Responses to HBV /
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502 $b Ph.D. $c Albany Medical College $d 2024.
520 $a Hepatitis B virus (HBV) infection is a leading cause of viral hepatitis despite the availability of a safe and effective preventative vaccine. A major unresolved question concerning HBV is why the immune system tolerates infection. The "stealth" nature of the virus largely evades the innate immune response, and the adaptive immune response sometimes becomes dysfunctional, leading to viral persistence manifesting as chronic HBV infection (CHB). CHB is a lifelong morbidity, and disease intervention is ineffective at achieving a complete cure due to the stability of the transcriptional template known as cccDNA. The immune system is a favorable target for theoretical HBV intervention because of the connection between viral control and the magnitude of the initial immune response to HBV. Modern approaches for HBV immunotherapy favor immune checkpoint inhibition (ICI) and therapeutic vaccination strategies. To achieve this vision, I aimed to understand the role of the CD4+ T cell in its ability to regulate both humoral and cellular immune responses to HBV.The CD4+ T cell is the master regulator of an immune response; it permits full activation of the innate and adaptive arms while simultaneously restraining them to prevent excessive inflammation through processes known as T cell help. Because of its potent immunomodulatory capacity, the CD4+ T cell is expected to be a key determinant in virological outcomes following HBV infection. Using a mouse model of HBV replication, I evaluated the contribution of CD4+ T cells in HBV establishment. It became clear that HBsAg seroconversion, part of the functional cure for HBV, depended on CD4+ T cell help. Notably, HBsAg persisted following the repopulation of the CD4+ T cell compartment, and persistence was reversible upon splenocyte transfer. These findings imply that CD4+ T cell dysfunction might be a driving force behind HBV persistence.During my investigation of the CD4+ T cell's response to HBV infection, the CD40-CD40L axis was identified as a critical determinant of HBsAg seroconversion. This observation implored us to investigate the therapeutic potential of the CD40 signaling pathway in HBV control. Unexpectedly, activation of the CD40 signaling pathway via agonistic α-CD40 led to HBV control in a CD8+ T cell-dependent manner. This effect was amplified when administered to mice devoid of CD4+ T cells and suggests that CD4+ T cells function to restrict HBV-specific CD8+ T cells in this particular context.In this work, I aimed to delineate CD4+ T cell responses to HBV infection. We discovered divergent, context-dependent roles of the CD4+ T cell response, both productive and otherwise. The key takeaways from the studies presented within this dissertation are that 1. T cell help in HBV is productive in facilitating HBsAg seroconversion; 2. CD4+ T cells exhibit a tendency to minimize inflammation, particularly in the liver; and 3. CD40 represents a feasible target for inducing an HBV-resolving CD8+ T cell response.
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650 4 $a Virology. $3 642304
650 4 $a Microbiology. $3 536250
653 $a Immunization
653 $a Therapeutic intervention
653 $a Hepatitis B virus
653 $a Chronic HBV infection
653 $a Immune checkpoint inhibition
690 $a 0982
690 $a 0720
690 $a 0410
710 2 $a Albany Medical College. $b Immunology & Microbial Disease (IMD). $e degree granting institution. $3 3828496
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773 0 $t Dissertations Abstracts International $g 85-10B.
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791 $a Ph.D.
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