Effective Control of Chronic γ-Herpesvirus Infection by Unconventional MHC Class Ia–Independent CD8 T Cells

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Abstract
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 Ia–dependent 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 γ-herpesvirus 68 (γHV68) infection via a robust expansion of β2-microglobulin (β2-m)-dependent, but CD1d-independent, unconventional CD8 T cells. These unconventional CD8 T cells expressed: (1) CD8αβ and CD3, (2) cell surface molecules associated with conventional effector/memory CD8 T cells, (3) TCRαβ with a significant Vβ4, Vβ3, and Vβ10 bias, and (4) the key effector cytokine interferon-γ (IFNγ). 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 β2-m–dependent, but Class Ia–independent, unconventional CD8 T cells can efficiently control chronic virus infection, implicating a role for β2-n–dependent 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 Ia–restricted T cells. In this paper the authors identify a β2-microglobulin–dependent but major histocompatibility complex (MHC) Class Ia– and CD1-independent class of CD8 T cells that effectively control chronic γ-herpesvirus infection in mice. The important point that should be of general interest to the readers of PLoS Pathogens is that an effective CD8 T cell response develops during chronic infection of mice lacking MHC Class Ia molecules. Enormous efforts have gone into characterizing the role of conventional CD8 T cells that recognize viral peptides together with MHC Class Ia molecules during chronic viral infection, and many vaccine approaches focus solely on this response. This paper shows that additional types of CD8 T cells can operate during chronic infection, and that indeed, conventional MHC Class Ia–restricted T cells may be dispensable for control of chronic herpesvirus infection. The authors believe this is a fundamentally important point because it raises the question of whether unconventional CD8 T cells are important for control of other chronic viral infections such as infection with HIV, Hepatitis C virus, Hepatitis B virus, or human herpesviruses.