An MHC class Ib–restricted CD8 T cell response confers antiviral immunity

Abstract

Although immunity against intracellular pathogens is primarily provided by CD8 T lymphocytes that recognize pathogen-derived peptides presented by major histocompatibility complex (MHC) class Ia molecules, MHC class Ib–restricted CD8 T cells have been implicated in antiviral immunity. Using mouse polyoma virus (PyV), we found that MHC class Ia–deficient (Kb−/−Db−/−) mice efficiently control this persistently infecting mouse pathogen. CD8 T cell depletion mitigates clearance of PyV in Kb−/−Db−/− mice. We identified the ligand for PyV-specific CD8 T cells in Kb−/−Db−/− mice as a nonamer peptide from the VP2 capsid protein presented by Q9, a member of the β2 microglobulin–associated Qa-2 family. Using Q9-VP2 tetramers, we monitored delayed but progressive expansion of these antigen-specific CD8αβ T cells in Kb−/−Db−/− mice. Importantly, we demonstrate that Q9-VP2–specific CD8 T cells more effectively clear wild-type PyV than a VP2 epitopenull mutant PyV. Finally, we show that wild-type mice also generate Q9-restricted VP2 epitope–specific CD8 T cells to PyV infection. To our knowledge, this is the first evidence for a defined MHC class Ib–restricted antiviral CD8 T cell response that contributes to host defense. This study motivates efforts to uncover MHC class Ib–restricted CD8 T cell responses in other viral infections, and given the limited polymorphism of MHC class Ib molecules, it raises the possibility of developing peptide-based viral vaccines having broad coverage across MHC haplotypes.

Memory T cell inflation: understanding cause and effect

“…Inflating CD8 + T cells in MCMV infection are mostly effector memory cells displaying little or no expression of co-stimulatory molecules such as CD27 and CD28 or receptors for the homeostatic cytokines IL-7 and IL-15 [8,9]. By contrast, CD8 + T cells specific for PyV reach stable high frequencies, express receptors for both IL-7 and IL-2 and are maintained in the absence of homeostatic proliferation [74]. It is not clear if the different phenotypes are related to differences in presentation by MHC 1a and MHC 1b molecules or in host-virus interaction or in different levels of antigen persistence.…”

TCR-MHC docking orientation: natural selection, or thymic selection?

“…helper MHCI-restricted cells coming out in MHCII deficient mice [74]. Interestingly, T cells selected on nonclassical MHC (Class Ib molecules, in the absence of MHCI or MHCII) bear a repertoire of TCR that is similar in diversity to that selected on wild type MHCI, just a smaller sample [65,75]. What would be the coevolutionary process that would allow for this to occur since class Ib-restricted T cells are most often a small percentage of normal T cells?…”

Peptide Immunization Elicits Polyomavirus-Specific MHC Class Ib-Restricted CD8 T Cells in MHC Class Ia Allogeneic Mice

“…It is important to note that Q9:VP2.139-specific CD8 T cells are detected in only a third of B6 mice infected with MPyV, with Q9:VP2.139 tetramer + CD8 T cells first detected at day 8 p.i. (31). In this experimental setup, most VP2.129 peptide-immunized mice produced a Q9:VP2.139-specific CD8 T cell response by 6 days after MPyV inoculation.…”

“…), we recently discovered a class Ib-restricted CD8 T cell response that confers protection against MPyV infection (31). A peptide derived from amino acids 139-147 of the VP2 capsid protein (VP2.139; HALNVVHDW) binds Q9, a ß 2 m-associated MHC class I molecule encoded in the mouse Qa-2 locus.…”