Genetic disruption of CD8⁺ Treg activity enhances the immune response to viral infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 52; pp. 21089 - 21094
• Main Authors: Holderried, Tobias A. W., Lang, Philipp A., Kim, Hye-Jung, Cantor, Harvey
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.12.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Adoptive Transfer; Animals; Antivirals; B lymphocytes; Biological Sciences; CD8-Positive T-Lymphocytes - immunology; Cellular immunity; DNA Virus Infections - immunology; Flow Cytometry; Genetics; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Immune response; Immune system; Immunity, Cellular - genetics; Immunology; Infections; Lymphocytes; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Mutation - genetics; Natural killer T cells; Pathology; Rodents; Statistics, Nonparametric; T lymphocytes; T-Lymphocytes, Regulatory - immunology; Viral infections; Viruses; killer cell Ig-like receptor; immune regulation; T-cell exhaustion
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1320999110

The immunological interactions that regulate the T-cell response to chronic viral infection are insufficiently understood. Here we study a cellular interaction that may enhance the antiviral immune response and constrain immunopathology. We analyze the contribution of Qa-1-restricted CD8 ⁺ regulatory T cells (Treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. These CD8 ⁺ Treg cells recognize and eliminate target cells through an interaction with the murine class Ib MHC molecule Qa-1 (HLA-E in humans). Using Qa-1 mutant mice (B6.Qa-1-D227K [B6-DK]) that harbor a single mutation that abrogates binding of Qa-1 peptide to the CD8–TCR (T-cell receptor) complex, we show that disruption of immune suppression mediated by CD8 ⁺ Treg cells results in robust antiviral immune responses in both acute and chronic viral infection. Enhanced antiviral responses of B6-DK mice were accompanied by increased control of virus, reduced tissue inflammation in the acute phase, and dramatic alleviation of disease in the chronic phase. In addition, CD8 ⁺ effector T cells in B6-DK mice displayed a less exhausted phenotype characterized by decreased expression of programmed cell death 1 (PD-1), LAG3 (CD223), and 2B4 (CD244) and increased expression of NKG2D (CD314) and killer cell lectin-like receptor subfamily G member 1 (KLRG1). Enhanced antiviral immunity in B6-DK mice reflected, in part, reduced inhibition of CD8 ⁺ effector cells by CD8 ⁺ Treg cells. These findings indicate that direct inhibition of effector CD8 ⁺ T cells by Qa-1-restricted CD8 ⁺ Treg cells results in increased disease severity and delayed recovery. These data suggest that depletion or inactivation of CD8 ⁺ Treg cells represents a potentially effective strategy to enhance protective immunity to chronic viral infection.