CD8⁺ T Cell Exhaustion During Persistent Viral Infection is Regulated Independently of the Virus-Specific T Cell Receptor

Abstract

During chronic viral infections, responses by virus-specific CD8⁺ T cells become marginalized by the acquisition of functional defects and reduced cell numbers in a process defined as T cell exhaustion. Similarly, T cell tolerance to self-antigen is also characterized by impaired effector function and eventual deletion of self-reactive T cells. Induction of both tolerance and exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective in these distinct environments. We previously demonstrated that tolerant self-reactive CD8⁺ T cells expressing dual-T cell receptors (i.e., dual-TCR) could be rescued by immunization through a second TCR specific for a foreign antigen. These data revealed that T cell tolerance was regulated at the level of the self-reactive TCR. Here, dual-TCR CD8⁺ T cells were used to examine if exhaustion during persistent viral infection could be rescued by an analogous strategy of immunization through a second TCR not involved in recognition of virus. In direct contrast to the rescue achievable in tolerant CD8⁺ T cells, exhausted T cells were equally impaired through both TCR. These findings suggest that exhaustion is maintained by defects downstream of the virus-specific TCR, and establish that exhaustion and tolerance are distinctly regulated states of T cell dysfunction.

• CD8⁺ T cells
• Dual-T cell Receptor
• Chronic Viral Infection
• Exhaustion
• Tolerance

ACKNOWLEDGMENTS

The authors would like to thank Dr. Mark Buller and Jill Schriewer for technical guidance with LCMV infections, and Sherri Koehm and Joy Eslick for technical assistance with flow cytometry and sorting. R.M.T is supported by a grant from the National Institutes of Health/NIAID (R01AI087764) and by an Investigator Award from the Cancer Research Institute.

Declaration of interest

The authors declare no commercial or financial conflict of interest. The authors alone are responsible for the content and writing of the paper.