Investigating the Requirements for Expansion and Maintenance of a Mouse Polyomavirus-Specific MHC Class Ib-Restricted CD8 T Cell Response Open Access

Abstract

Major Histocompatibility Complex (MHC) class I molecules present intracellular peptides to CD8 T cells to mediate pathogen surveillance. In contrast to the highly polymorphic MHC class Ia molecules, the non-classical MHC class Ib proteins are oligomorphic or monomorphic. It is increasingly apparent that MHC class Ib molecules can participate in antigen presentation to CD8 T cells. If CD8 T cells can recognize an identical peptide presented in an MHC class Ib molecule in allogenic hosts, this would allow for safe, cost-effective peptide-based vaccines which could induce CD8 T cell immunity in an outbred population.

We recently identified a class Ib-restricted CD8 T cell response specific for an epitope from the VP2 capsid protein of mouse polyomavirus (MPyV). The VP2.139-147 peptide, presented on Q9, a class Ib Qa-2 family protein, is protective against MPyV in class Ia-deficient mice (B6.K^b-/-D^b-/-). MPyV infection of B6.K^b-/-D^b-/- mice initiates a 3-month long inflation of Q9:VP2.139-specific αβ CD8 T cells. This is followed by antigen-independent maintenance of the clone, with no defined contraction. It is unclear what factors drive the long inflationary kinetics or the antigen-independent maintenance of the Q9:VP2.139-specific CD8 T cells. We hypothesized that, parallel with the requisite for antigen, the Q9:VP2.139-specific response would depend on CD4 help and CD28/CD40L costimulation for expansion, but not for maintenance. However, we found that although CD4 help and autochthonous CD28 costimulation are required for expansion, CD4 help continues to be required for maintenance.

Because Q9 is non-polymorphic, we hypothesized that a Q9:VP2.139-specific CD8 T cell response could be generated in MHC allotypic Q9+ mouse strains. Mice of the H-2^s and H-2^g7 haplotypes are Qa-2+. We were able to elicit Q9:VP2.139-specific CD8 T cells in mice of both haplotypes after a prime-boost regimen with VP2.139 peptide. We demonstrate that Q9:VP2.139-specific CD8 T cells are protective against MPyV in MHC class Ia allogenic mice. These results imply that class Ib MHC molecules can contribute to protective immunity in mice of different MHC haplotypes.

Table of Contents

Table of Contents

Abstract

Chapter 1: Introduction...1

Figure 1.1: MPyV encodes six proteins in overlapping reading frames...72
Figure 1.2: Different peptide:Qa-1b ligands trigger varied responses by Qa-1b-specific CD8 T cells...73

Chapter 2: MHC Class Ib-Restricted CD8 T Cells Differ in Dependence on CD4 T Cell Help and CD28 Costimulation over the Course of Mouse Polyomavirus Infection...74

Figure 2.1: Q9:VP2.139-specific cells depend on CD4 T cell help for expansion...110
Figure 2.2: Expansion of Q9:VP2.139-specific CD8 T cells depends on CD28 and CD40L costimulation...111
Figure 2.3: Expansion of Q9:VP2.139-specific CD8 T cells depends on CD28 costimulation...112
Figure 2.4: Q9:VP2.139-specific cells depend on intrinsic CD28 costimulation for expansion...113
Figure 2.5: Q9:VP2.139-specific cells do not depend on costimulation for maintenance...114
Figure 2.6: Q9:VP2.139-specific cells depend on CD4 help for maintenance...115
Figure 2.7: Exogenous IL-2 therapy does not prevent loss of the Q9:VP2.139-specific population following maintenance-phase CD4 depletion...116
Figure 2.8: Phenotypic characterization of Q9:VP2.139-specific CD8 T cells in B6.K^b-/-D^b-/- mice during expansion and maintenance phases...117

Chapter 3: Peptide Immunization Elicits Polyomavirus-specific MHC class Ib-restricted CD8 T cells that Confer Protection in MHC Class Ia Allogeneic Mice...118

Figure 3.1: VP2.139 peptide-immunized NOD and SJL mice generate Q9:VP2.139-specific CD8 T cell responses...132
Figure 3.2: Q9:VP2.139-specific CD8 T cells protect against MPyV infection in peptide-immunized NOD mice...133

Chapter 4: Discussion...134

Figure 4.1: IFN-γ production by Q9:VP2.139-specific CD8 T cells increases with peptide dose and with time p.i....180

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
Keyword	Mouse Polyomavirus Persistent Viral Infection MHC Class Ib CD8 T cells Retrogenic T Cells
Committee Chair / Thesis Advisor	Lukacher, Aron E, Emory University
Committee Members	Evavold, Brian, Emory University Ford, Mandy L, Emory University Kohlmeier, Jacob, Emory University Mittler, Robert S, Emory University

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