A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

被引：293

作者：

Dutzan, Nicolas ^{[1
,2
]}

Kajikawa, Tetsuhiro ^{[3
]}

Abusleme, Loreto ^{[1
,2
]}

Greenwell-Wild, Teresa ^{[1
]}

Zuazo, Carlos E. ^{[1
]}

Ikeuchi, Tomoko ^{[1
]}

Brenchley, Laurie ^{[1
]}

Abe, Toshiharu ^{[3
]}

Hurabielle, Charlotte ^{[4
,5
]}

Martin, Daniel ^{[6
]}

Morell, Robert J. ^{[6
]}

Freeman, Alexandra F. ^{[7
]}

Lazarevic, Vanja ^{[8
]}

Trinchieri, Giorgio ^{[9
]}

Diaz, Patricia I. ^{[10
]}

Holland, Steven M. ^{[7
]}

Belkaid, Yasmine ^{[4
]}

Hajishengallis, George ^{[3
]}

Moutsopoulos, Niki M. ^{[1
]}

机构：

[1] NIDCR, Oral Immun & Inflammat Unit, NIH, Bethesda, MD 20892 USA

[2] Univ Chile, Fac Dent, Santiago 8380492, Chile

[3] Univ Penn, Dept Microbiol, Penn Dent Med, Philadelphia, PA 19104 USA

[4] NIAID, Mucosal Immunol Sect, Lab Parasit Dis, NIH, Rockville, MD 20892 USA

[5] Univ Paris Diderot, Hop St Louis, INSERM, U976, F-75010 Paris, France

[6] NIDCD, Genom & Computat Biol Core, NIH, Bethesda, MD 20892 USA

[7] NIAID, LCIM, NIH, Bethesda, MD 20892 USA

[8] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[9] NCI, CCR, Canc & Inflammat Program, NIH, Bethesda, MD 20892 USA

[10] UConn Hlth, Sch Dent Med, Farmington, CT 06030 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2018年 / 10卷 / 463期

关键词：

INFLAMMATORY BONE LOSS; HYPER-IGE SYNDROME; PERIODONTAL-DISEASE; PORPHYROMONAS-GINGIVALIS; LYMPHOID-CELLS; IMMUNITY; STAT3; INTERLEUKIN-17; PATHOGENICITY; HOMEOSTASIS;

D O I：

10.1126/scitranslmed.aat0797

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (T(H)17) cells in human periodontitis. Phenocopying humans, T(H)17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral T(H)17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)-dependent manner, periodontitis-associated expansion of T(H)17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. T(H)17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of T(H)17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in T(H)17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of T(H)17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

引用

页数：12

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