Control of virus infection is mediated in part by major histocompatibility complex (MHC) Class Ia presentation of viral peptides
to conventional CD8 T cells. Although important, the absolute requirement for MHC Class Iadependent CD8 T cells for control of chronic virus
infection has not been formally demonstrated. We show here that mice lacking MHC Class Ia molecules (Kb/xDb/ mice) effectively control chronic -herpesvirus 68 (HV68) infection via a robust expansion of 2-microglobulin (2-m)-dependent, but CD1d-independent,
unconventional CD8 T cells. These unconventional CD8 T cells expressed: (1) CD8 and CD3, (2) cell surface molecules associated with conventional effector/memory CD8 T cells, (3) TCR with a significant V4, V3, and V10 bias, and (4) the key effector cytokine interferon- (IFN). Unconventional CD8 T cells utilized a diverse TCR repertoire, and CDR3 analysis suggests that some of that repertoire may be utilized even in the presence of conventional CD8 T cells. This is the first demonstration to our knowledge that 2-mdependent, but Class Iaindependent, unconventional CD8 T cells can efficiently control chronic virus infection, implicating a role for 2-ndependent non-classical MHC molecules in control of chronic viral infection. We speculate that similar unconventional CD8 T cells may be able to control of other chronic viral infections, especially when viruses evade immunity by inhibiting generation of Class Iarestricted T cells.