Characterization of the CD4+ T Cell Response to Mouse Polyomavirus Infection Open Access

Lin, Eugene (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/g732d9837?locale=en
Published

Abstract

Virus-specific CD4+ T cells optimize anti-viral responses by providing help for anti-viral humoral responses and CD8+ T cells. However, little is known about the impact of low-level persistent infections on the fate and function of virus-specific CD4+ T cells. Using a mouse polyomavirus (MPyV) infection model, we identified two dominant CD4+ T cell populations specific for epitopes derived from the nonstructural LT antigen and VP1, the major viral capsid protein. These MPyV-specific CD4+ T cells vary in terms of their magnitude, functional profile, and phenotype during acute and persistent phases of infection. Employing a minimally myeloablative mixed bone marrow chimerism approach, we further show that naïve virus-specific CD4+ T cells are primed de novo during persistent virus infection.

After clearance of an acute viral infection, memory T cells develop that survive in the absence of antigen and can mount robust recall responses against challenge infection. During chronic high load infections, however, virus-specific CD8+ T cells become dependent on antigen for their survival. Whether T cells formed during low-level persistent infections require antigen for their survival is less clear. In this study, we developed a novel approach to ablate MPyV replication during persistent infection. We generated a recombinant MPyV in which genes critical for replication are floxed (A2.Flx). Cre-mediated deletion of A2.Flx leads to reductions in viral levels both in vitro and in mice expressing Cre constitutively. Utilizing mice expressing a tamoxifen-inducible Cre, we found that reduction of viral replication during persistent A2.Flx infection had a variable impact on virus-specific CD4+ and CD8+ T cells. While some MPyV-specific T cell populations were notably reduced, others were maintained but adopted a more central memory T cell phenotype. Our data suggests that antigen is not necessarily required for survival of MPyV-specific memory T cells and those cells can be redirected toward a phenotype associated with antigen-independent survival following reductions in viral antigen.



Table of Contents

Table of Contents

Abstract
List of Figures

Chapter 1: Introduction
I. Anti-viral immunity and CD4+ T cells
II. Persistent infection impacts T cell memory and function
III. Polyomavirus pathogenesis
IV. Adaptive immunity to mouse polyomavirus


Chapter 2: Heterogeneity among viral antigen-specific CD4+ T cells and their de novo recruitment during persistent polyomavirus infection

Chapter 3: Assessing the impact of persistent infection on polyomavirus-specific T cells

Chapter 4: Discussion

About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Subfield / Discipline
Degree
Submission
Language
  • English
Research field
Keyword
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files