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Tryptophan Catabolism by Indoleamine 2,3-Dioxygenase 1 Alters the Balance of T H 17 to Regulatory T Cells in HIV Disease

2010; American Association for the Advancement of Science; Volume: 2; Issue: 32 Linguagem: Inglês

10.1126/scitranslmed.3000632

1946-6242

David Favre, Jeff E. Mold, Peter W. Hunt, Bittoo Kanwar, P’ng Loke, Lillian Seu, Jason D. Barbour, Margaret M. Lowe, Anura Jayawardene, Francesca Aweeka, Yong Huang, Daniel C. Douek, Jason M. Brenchley, Jeffrey N. Martin, Frederick Hecht, Steven G. Deeks, Joseph M. McCune,

Stress Responses and Cortisol

The pathogenesis of human and simian immunodeficiency viruses is characterized by CD4(+) T cell depletion and chronic T cell activation, leading ultimately to AIDS. CD4(+) T helper (T(H)) cells provide protective immunity and immune regulation through different immune cell functional subsets, including T(H)1, T(H)2, T regulatory (T(reg)), and interleukin-17 (IL-17)-secreting T(H)17 cells. Because IL-17 can enhance host defenses against microbial agents, thus maintaining the integrity of the mucosal barrier, loss of T(H)17 cells may foster microbial translocation and sustained inflammation. Here, we study HIV-seropositive subjects and find that progressive disease is associated with the loss of T(H)17 cells and a reciprocal increase in the fraction of the immunosuppressive T(reg) cells both in peripheral blood and in rectosigmoid biopsies. The loss of T(H)17/T(reg) balance is associated with induction of indoleamine 2,3-dioxygenase 1 (IDO1) by myeloid antigen-presenting dendritic cells and with increased plasma concentration of microbial products. In vitro, the loss of T(H)17/T(reg) balance is mediated directly by the proximal tryptophan catabolite from IDO metabolism, 3-hydroxyanthranilic acid. We postulate that induction of IDO may represent a critical initiating event that results in inversion of the T(H)17/T(reg) balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease.