Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system.
Inflammatory bowel disease (IBD) has been attributed to overexuberant host immunity or the emergence of harmful intestinal flora. The transcription factor T-bet orchestrates inflammatory genetic programs in both adaptive and innate immunity. We describe a profound and unexpected function for T-bet in influencing the behavior of host inflammatory activity and commensal bacteria. T-bet deficiency in the innate immune system results in spontaneous and communicable ulcerative colitis in the absence of adaptive immunity and increased susceptibility to colitis in immunologically intact hosts. T-bet controls the response of the mucosal immune system to commensal bacteria by regulating TNF-alpha production in colonic dendritic cells, critical for colonic epithelial barrier maintenance. Loss of T-bet influences bacterial populations to become colitogenic, and this colitis is communicable to genetically intact hosts. These findings reveal a novel function for T-bet as a peacekeeper of host-commensal relationships and provide new perspectives on the pathophysiology of IBD.
Garrett
Wendy S
WS
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Lord
Graham M
GM
Punit
Shivesh
S
Lugo-Villarino
Geanncarlo
G
Mazmanian
Sarkis K
SK
Ito
Susumu
S
Glickman
Jonathan N
JN
Glimcher
Laurie H
LH
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003093:Colitis, Ulcerative / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D053645:Interleukin-2 Receptor alpha Subunit; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha