title: Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection.
abstract: 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.
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02215.
authors: Tobias A W
authors: TA
authors: Holderried
authors: Philipp A
authors: PA
authors: Lang
authors: Hye-Jung
authors: HJ
authors: Kim
authors: Harvey
authors: H
authors: Cantor
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004266:DNA Virus Infections / Q000276:immunology*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; C032907:Q surface antigens
keywords: T-cell exhaustion; immune regulation; killer cell Ig-like receptor