Qa-1-Restricted CD8+ T Cells Can Compensate for the Absence of Conventional T Cells during Viral Infection

The role of non-classical T cells during viral infection remains poorly understood. Using the well-established murine model of CMV infection (MCMV) and mice deficient in MHC class Ia molecules, we found that non-classical CD8+ T cells robustly expand after MCMV challenge, become highly activated effectors, and are capable of forming durable memory. Interestingly, although these cells are restricted by MHC class Ib molecules, they respond similarly to conventional T cells. Remarkably, when acting as the sole component of the adaptive immune response, non-classical CD8+ T cells are sufficient to protect against MCMV-induced lethality. We also demonstrate that the MHC class Ib molecule Qa-1 (encoded by H2-T23) restricts a large, and critical, portion of this population. These findings reveal a potential adaptation of the host immune response to compensate for viral evasion of classical T cell immunity. [Display omitted] •MHC class Ib-restricted CD8+ T cells participate during MCMV infection•This population behaves like conventional T cells, rather than innate-like T cells•These cells can protect against MCMV-induced lethality without other T and B cells•Qa-1-restricted cells are an essential component for the non-classical response Anderson et al. describe a heterogenous population of non-classical CD8+ T cells responding to MCMV. Importantly, this population can protect mice from MCMV-induced lethality in the absence of other adaptive immune cells. Among the MHC class Ib-restricted CD8+ T cells responding, Qa-1-specific cells are required for protection.