期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 2, 期 32, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3000632
关键词
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资金
- Intramural NIH HHS Funding Source: Medline
- NCRR NIH HHS [UL1 RR024131] Funding Source: Medline
- NIAID NIH HHS [AI069994, K01 AI066917, K23 AI065244, P30 AI022763, R01 K23 AI065244, R37 AI40312, P30 AI27763, R37 AI040312, P01 AI071713, P30 AI027763, K24 AI069994, R01 AI066917] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007762, K08 DK083334, K08 DK083334-01A1, K24 DK060617] Funding Source: Medline
- NIH HHS [DP1 OD000329, DPI OD00329] Funding Source: Medline
- NIMH NIH HHS [P30 MH59037] Funding Source: Medline
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.
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