HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation.
Infection by the human immunodeficiency virus (HIV) is characterized by functional impairment and chronic activation of T lymphocytes, the causes of which are largely unexplained. We cultured peripheral blood mononuclear cells (PBMC) from HIV-uninfected donors in the presence or absence of HIV. HIV exposure increased expression of the activation markers CD69 and CD38 on CD4 and CD8 T cells. IFN-alpha/beta, produced by HIV-activated plasmacytoid dendritic cells (pDC), was necessary and sufficient for CD69 and CD38 upregulation, as the HIV-induced effect was inhibited by blockade of IFN-alpha/beta receptor and mimicked by recombinant IFN-alpha/beta. T cells from HIV-exposed PBMC showed reduced proliferation after T cell receptor stimulation, partially prevented by 1-methyl tryptophan, a competitive inhibitor of the immunesuppressive enzyme indoleamine (2,3)-dioxygenase (IDO), expressed by HIV-activated pDC. HIV-induced IDO inhibited CD4 T cell proliferation by cell cycle arrest in G1/S, and prevented CD8 T cell from entering the cell cycle by downmodulating the costimulatory receptor CD28. Finally, the expression of CHOP, a marker of the stress response activated by IDO, was upregulated by HIV in T cells in vitro and is increased in T cells from HIV-infected patients. Our data provide an in vitro model for HIV-induced T cell dysregulation and support the hypothesis that activation of pDC concomitantly contribute to phenotypic T cell activation and inhibition of T cell proliferative capacity during HIV infection.
Boasso
Adriano
A
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. a.boasso@imperial.ac.uk
Hardy
Andrew W
AW
Anderson
Stephanie A
SA
Dolan
Matthew J
MJ
Shearer
Gene M
GM
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis*; D007519:Isoantigens / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014364:Tryptophan / Q000378:metabolism*; D000099192:CD69 Antigens
D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007370:Interferon Type I; D007519:Isoantigens; D037181:Lectins, C-Type; D014364:Tryptophan; D000099192:CD69 Antigens