Absence of an Immunodominant MHC Class Ia-Restricted Epitope Elicits a Compensatory MHC Class Ib-Restricted CD8+ T Cell Response to Mouse Polyomavirus CNS Infection

Open Access
- Author:
- Jaiprakash, Amrita
- Graduate Program:
- Anatomy
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- March 21, 2017
- Committee Members:
- Aron Lukacher, Thesis Advisor/Co-Advisor
Patricia McLaughlin, Committee Member
Todd Schell, Committee Member
James Connor, Committee Member - Keywords:
- Polyomavirus
MHC
MHC class Ib
Progressive Multifocal Leukoencephalopathy
Non-classical MHC
Mouse Polyomavirus - Abstract:
- CD8+ T lymphocytes are the major immunocytes responsible for host defense against viral infection. The ligand for a CD8+ T cell receptor consists of a short peptide derived from a viral protein bound to a heterodimeric molecule encoded within the major histocompatibility complex (MHC). Most MHC molecules are highly polymorphic, a property responsible for the extensive repertoire of peptides available for recognition by T cells; these MHC molecules are designated MHC-Ia. Given the dynamic interplay between a host’s immune system and viruses, viruses often mutate antigenic peptides to prevent binding to MHC-Ia molecules and thereby evade recognition by antiviral CD8+ T cells. Recently, non- and oligo-morphic MHC-Ib molecules have been described as adept presenters of microbial peptides to CD8+ T cells across most outbred members of a given species. Our group recently uncovered a protective MHC-Ib-restricted CD8+ T cell response to mouse polyomavirus (MuPyV), a natural, persistent mouse pathogen; however, this response was only detected in mice lacking MHC-Ia molecules. In this study, we asked whether ablation of the dominant MHC-Ia-restricted viral peptide epitope in MuPyV-infected immunocompetent mice would allow emergence of CD8+ T cells specific for a minor MuPyV capsid protein derived epitope, Q9:VP2.139-147. This restriction element is part of the MHC-Ib family and is shared across inbred mouse strains with varying MHC-Ia alleles. To test the proposed hypothesis, we inoculated C57BL/6 mice intracerebrally (i.c.) with a mutant MuPyV lacking the dominant CD8+ T cell epitope Db:LT359. The i.c. route of inoculation causes robust recruitment of anti-MuPyV T cells to the brain, an organ targeted by the human JC polyomavirus to cause the often-fatal demyelinating disease, progressive multifocal leukoencephalopathy. Using this LT359null mutant virus and assessing T cell responses by intracellular cytokine staining (ICS), we uncovered a strong MHC-Ib-restricted CD8+ T cell response to the Q9:VP2.139 epitope. Notably, VP2.139+ CD8+ T cells were observed in the infected brain, but not the spleen, although virus levels were similar in both organs. In contrast, MuPyV-specific CD8+ T cells recognizing subdominant MHC-Ia epitopes were detected in both the brain and spleen. The compensatory increase by a non-classical MHC-Ib-restricted CD8+ T cell population suggests that MHC-Ib-restricted CD8+ T cells may serve as a backup host defense mechanism for polyomaviruses infecting the CNS that mutate viral peptides presented by MHC-Ia molecules.