Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses.
The intestinal tract is in intimate contact with the commensal microflora. Nevertheless, how commensals communicate with cells to ensure immune homeostasis is still unclear. In this study, we found that gut flora DNA (gfDNA) plays a major role in intestinal homeostasis through Toll-like receptor 9 (TLR9) engagement. Tlr9(-/-) mice displayed increased frequencies of CD4(+)Foxp3(+) regulatory T (Treg) cells within intestinal effector sites and reduced constitutive IL-17- and IFN-gamma-producing effector T (Teff) cells. Complementing this, gfDNA limited lamina propria dendritic cell-induced Treg cell conversion in vitro. Further, Treg/Teff cell disequilibrium in Tlr9(-/-) mice led to impaired immune responses to oral infection and to oral vaccination. Impaired intestinal immune responses were recapitulated in mice treated with antibiotics and were reversible after reconstitution with gfDNA. Together, these data point to gfDNA as a natural adjuvant for priming intestinal responses via modulation of Treg/Teff cell equilibrium.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Jason A
JA
Hall
Nicolas
N
Bouladoux
Cheng Ming
CM
Sun
Elizabeth A
EA
Wohlfert
Rebecca B
RB
Blank
Qing
Q
Zhu
Michael E
ME
Grigg
Jay A
JA
Berzofsky
Yasmine
Y
Belkaid
D000276:Adjuvants, Immunologic; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004269:DNA, Bacterial / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D007422:Intestines / Q000382:microbiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D020381:Interleukin-17; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma