Proceedings of the National Academy of Sciences of the United States, Dec 24, 2013, Vol.110(52), p.21089(6)
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.sup.+] regulatory T cells (Treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. These [CD8.sup.+] 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 X 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.sup.+] 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.sup.+] 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.sup.+] effector cells by [CD8.sup.+] Treg cells. These findings indicate that direct inhibition of effector [CD8.sup.+] T cells by Qa-1-restricted [CD8.sup.+] Treg cells results in increased disease severity and delayed recovery. These data suggest that depletion or inactivation of [CD8.sup.+] Treg cells represents a potentially effective strategy to enhance protective immunity to chronic viral infection. T-cell exhaustion | killer cell Ig-like receptor | immune regulation www.pnas.org/cgi/doi/10.1073/pnas.1320999110
Virus Diseases -- Research ; Virus Diseases -- Analysis ; Virus Diseases -- Health Aspects ; T Cells -- Analysis ; T Cells -- Health Aspects ; Genetic Research -- Analysis ; Genetic Research -- Health Aspects ; Antiviral Agents -- Research ; Antiviral Agents -- Analysis ; Antiviral Agents -- Health Aspects ; Hla Antigens -- Analysis ; Hla Antigens -- Health Aspects ; Immune Response -- Analysis ; Immune Response -- Health Aspects
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