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The Role of CD4+ T Cell Help in the Generation of Intrahepatic CD8+ T Cell Subsets During an HCV-Related Rodent Hepacivirus Infection /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Role of CD4+ T Cell Help in the Generation of Intrahepatic CD8+ T Cell Subsets During an HCV-Related Rodent Hepacivirus Infection // Jarrett Lopez-Scarim.
作者:	Lopez-Scarim, Jarrett,
面頁冊數:	1 electronic resource (190 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
標題:	Immunology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=32038479
ISBN:	9798280782662

The Role of CD4+ T Cell Help in the Generation of Intrahepatic CD8+ T Cell Subsets During an HCV-Related Rodent Hepacivirus Infection /
Lopez-Scarim, Jarrett,

The Role of CD4+ T Cell Help in the Generation of Intrahepatic CD8+ T Cell Subsets During an HCV-Related Rodent Hepacivirus Infection /Jarrett Lopez-Scarim. - 1 electronic resource (190 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Hepatitis C virus (HCV) infection typically results in a chronic infection defined by progressive liver damage that can lead to cirrhosis and cancer. Despite the introduction of direct-acting antivirals capable of curing chronic HCV infection, the elimination of HCV is still a significant challenge for public health officials. The creation of an effective and affordable HCV vaccine would be a powerful tool in the fight against HCV. Understanding the adaptive immune response that leads to the clearance of hepatic viral infections would aid in the development and screening of vaccine candidates. However, attempts to study the immune response to hepatitis C virus infection have been limited by the exclusively hepatotropic nature of the virus and the lack of small animal models. The introduction of a mouse infection model utilizing HCV-related Norway rat hepacivirus (NrHV) has created new opportunities for investigating intrahepatic immune responses. This model's reliance on CD8+ T cells and CD4+ T cells for viral clearance makes it ideal for studying the intrahepatic T cell response to hepatic viral infections. Using this model, we characterized the intrahepatic CD8+ T cell response and tested our hypothesis that CD4+ T cells' essential role in the clearance of NrHV infection is due to the support they provide during the priming of CD8+ T cells.Using major histocompatibility complex class I tetramers for two distinct NrHV epitopes, we performed full spectrum flow cytometry to characterize the NrHV-specific intrahepatic CD8+ T cell response in C57BL/6J mice during primary NrHV infection. We also examined the memory populations formed after viral clearance. Additionally, we utilized peptides corresponding to these epitopes to test the antiviral responses mounted by NrHV-specific CD8+ T cells. Antibody-mediated depletion of CD4+ T cells helped establish the kinetics CD4+ T cell help during NrHV infection. We also investigated CD40-CD40L interactions, a form of CD4+ T cell help which plays a critical role in the maturation of CD8+ T cell priming dendritic cells. The antibody-mediated neutralization of CD40-CD40L interactions allowed us to investigate this potential mechanism. Our results show that the CD8+ T cell response to NrHV was defined by a sharp increase in NrHV-specific CD8+ T cells that was correlated with the resolution of infection by day 21 of infection. Our analysis revealed CD8+ T cell populations specific to two distinct NrHV epitopes, which differed in their kinetics, effector functions, and phenotype. We also discovered that CD4+ T cell depletion or CD40L neutralization during CD8+ T cell priming resulted in a reduction in short lived effector cells, the absence of polyfunctionality, and delayed or prevented viral clearance. Furthermore, a unique CD8+ T cell subset expressing two tissue-residency associated proteins, CD103+ (an integrin-α that binds the adhesion molecule E-cadherin) and CD49a+ (an integrin-α that binds collagen) was discovered. This subset was only found in significant numbers within the liver. These CD103+ CD49a+ CD8+ T cells showed signs of a higher capacity for antiviral effector functions and were retained as a hepatic tissue-resident population after viral clearance. However, the absence of CD4+ T cells or CD40L-CD40 interactions during CD8+ T cell priming led to the loss of this subset.In summary, using the NrHV infection mouse model, we characterized the intrahepatic CD8+ T cell response to a hepatic viral infection. We determined that the polyfunctional and tissue-resident CD8+ T cell phenotypes seen during NrHV infection were dependent on CD4+ T cell help during priming. Furthermore, we discovered that CD40-CD40L interactions were the likely mechanism by which this help is provided. Overall, the NrHV infection model has allowed us to make significant progress in characterizing the CD8+ T cell responses that lead to viral resolution and identify the key immune interactions that shape the CD8+ T cell response. By investigating the causes of viral resolution, we hope to inform future vaccine design and contribute to the elimination of HCV.

English

ISBN: 9798280782662Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Animal model

The Role of CD4+ T Cell Help in the Generation of Intrahepatic CD8+ T Cell Subsets During an HCV-Related Rodent Hepacivirus Infection /
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520 $a Hepatitis C virus (HCV) infection typically results in a chronic infection defined by progressive liver damage that can lead to cirrhosis and cancer. Despite the introduction of direct-acting antivirals capable of curing chronic HCV infection, the elimination of HCV is still a significant challenge for public health officials. The creation of an effective and affordable HCV vaccine would be a powerful tool in the fight against HCV. Understanding the adaptive immune response that leads to the clearance of hepatic viral infections would aid in the development and screening of vaccine candidates. However, attempts to study the immune response to hepatitis C virus infection have been limited by the exclusively hepatotropic nature of the virus and the lack of small animal models. The introduction of a mouse infection model utilizing HCV-related Norway rat hepacivirus (NrHV) has created new opportunities for investigating intrahepatic immune responses. This model's reliance on CD8+ T cells and CD4+ T cells for viral clearance makes it ideal for studying the intrahepatic T cell response to hepatic viral infections. Using this model, we characterized the intrahepatic CD8+ T cell response and tested our hypothesis that CD4+ T cells' essential role in the clearance of NrHV infection is due to the support they provide during the priming of CD8+ T cells.Using major histocompatibility complex class I tetramers for two distinct NrHV epitopes, we performed full spectrum flow cytometry to characterize the NrHV-specific intrahepatic CD8+ T cell response in C57BL/6J mice during primary NrHV infection. We also examined the memory populations formed after viral clearance. Additionally, we utilized peptides corresponding to these epitopes to test the antiviral responses mounted by NrHV-specific CD8+ T cells. Antibody-mediated depletion of CD4+ T cells helped establish the kinetics CD4+ T cell help during NrHV infection. We also investigated CD40-CD40L interactions, a form of CD4+ T cell help which plays a critical role in the maturation of CD8+ T cell priming dendritic cells. The antibody-mediated neutralization of CD40-CD40L interactions allowed us to investigate this potential mechanism. Our results show that the CD8+ T cell response to NrHV was defined by a sharp increase in NrHV-specific CD8+ T cells that was correlated with the resolution of infection by day 21 of infection. Our analysis revealed CD8+ T cell populations specific to two distinct NrHV epitopes, which differed in their kinetics, effector functions, and phenotype. We also discovered that CD4+ T cell depletion or CD40L neutralization during CD8+ T cell priming resulted in a reduction in short lived effector cells, the absence of polyfunctionality, and delayed or prevented viral clearance. Furthermore, a unique CD8+ T cell subset expressing two tissue-residency associated proteins, CD103+ (an integrin-α that binds the adhesion molecule E-cadherin) and CD49a+ (an integrin-α that binds collagen) was discovered. This subset was only found in significant numbers within the liver. These CD103+ CD49a+ CD8+ T cells showed signs of a higher capacity for antiviral effector functions and were retained as a hepatic tissue-resident population after viral clearance. However, the absence of CD4+ T cells or CD40L-CD40 interactions during CD8+ T cell priming led to the loss of this subset.In summary, using the NrHV infection mouse model, we characterized the intrahepatic CD8+ T cell response to a hepatic viral infection. We determined that the polyfunctional and tissue-resident CD8+ T cell phenotypes seen during NrHV infection were dependent on CD4+ T cell help during priming. Furthermore, we discovered that CD40-CD40L interactions were the likely mechanism by which this help is provided. Overall, the NrHV infection model has allowed us to make significant progress in characterizing the CD8+ T cell responses that lead to viral resolution and identify the key immune interactions that shape the CD8+ T cell response. By investigating the causes of viral resolution, we hope to inform future vaccine design and contribute to the elimination of HCV.
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