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.
Highlights
A defining characteristic of herpesviruses is their ability to persist for the life of the infected host by establishing latent infection after acute infection is cleared
To begin to evaluate the role of Class Ia molecules during c-herpesvirus 68 (cHV68) infection, acute virus replication was compared in strains of mice 9 d after intraperitoneal injection of 106 plaque forming units (PFU) of wild-type cHV68
We present data in this paper demonstrating that unconventional CD8 T cells arise in infected Class Ia–deficient mice
Summary
A defining characteristic of herpesviruses is their ability to persist for the life of the infected host by establishing latent infection after acute infection is cleared. Many c-herpesviruses, including the human pathogens Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), and the murine pathogen c-herpesvirus 68 (cHV68), establish life-long latent infections within hematopoietic cells [1,2,3,4,5,6]. A second, long-term form of latency occurs 28–42 d after infection and is characterized by a lower efficiency of reactivation ex vivo, with approximately 10% of genome-bearing cells reactivating [23,25,30]. This long-term form of latency reflects a stable relationship between the virus and the host that is independent of both dose and route
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