Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection
Tobias A. W. Holderrieda,b,c,
Philipp A. Langc,
Hye-Jung Kima,b,1,2, and
Harvey Cantora,b,1,2
Author Affiliations
Contributed by Harvey Cantor, November 14, 2013 (sent for review October 25, 2013)
Significance
Cellular interactions that regulate the immune response of T cells to viral infection are poorly understood. Here we report that in the absence of activity of CD8 regulatory T-cells (CD8 Treg cells), antiviral immunity is enhanced and the deleterious effects of viral infection are constrained. Using a genetically modified mouse model that displays defective regulatory activity of CD8 Treg cells, the immune response against viruses was substantially enhanced during the acute and chronic phase of viral infection; this enhanced antiviral response prevented tissue damage associated with viral infection. This suggests that protective immunity to viral infection can be achieved by blocking the inhibitory effects of CD8 Treg cells and opens the possibility of unique approaches to treat 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.
1H.-J.K. and H.C. contributed equally to this work.
2To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: T.A.W.H., P.A.L., H.-J.K., and H.C. designed research; T.A.W.H. and H.-J.K. performed research; T.A.W.H., P.A.L., H.-J.K., and H.C. analyzed data; and T.A.W.H., P.A.L., H.-J.K., and H.C. wrote the paper.