Abstract
Disturbance of T-cell homeostasis could lead to intestinal inflammation. Naive CD4 T cells undergoing spontaneous proliferation, a robust proliferative response that occurs under severe lymphopenic conditions, differentiate into effector cells producing Th1- and/or Th17-type cytokines and induce a chronic inflammation in the intestine that resembles human inflammatory bowel disease. In this study, we investigated the key properties of CD4 T cells necessary to induce experimental colitis. α4β7 upregulation was primarily induced by mesenteric lymph node (mLN) resident CD11b(+) dendritic cell subsets via transforming growth factor beta (TGFβ)/retinoic acid-dependent mechanism. Interestingly, α4β7 expression was essential but not sufficient to induce inflammation. In addition to gut-homing specificity, expression of gut Ag specificity was also crucial. T-cell acquisition of the specificity was dramatically enhanced by the presence of γδ T cells, a population previously shown to exacerbate T-cell-mediated colitis. Importantly, interleukin (IL)-23-mediated γδ T cell stimulation was necessary to enhance colitogenicity but not gut antigen reactivity of proliferating CD4 T cells. These findings demonstrate that T-cell colitogenicity is achieved through multiple processes, offering a therapeutic rationale by intervening these pathways.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Colitis / immunology*
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Colitis / metabolism
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Colitis / pathology
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Dendritic Cells / cytology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Gastrointestinal Tract / immunology*
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Gastrointestinal Tract / metabolism
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Gastrointestinal Tract / pathology
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Genes, T-Cell Receptor beta / physiology
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Homeodomain Proteins / physiology
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Humans
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / pathology
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Integrins / metabolism*
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Interleukin-16 / physiology
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Interleukin-23 Subunit p19 / physiology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Mesenteric Veins / immunology
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Mesenteric Veins / metabolism
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Mesenteric Veins / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Receptors, Antigen, T-Cell, gamma-delta / genetics
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Receptors, Antigen, T-Cell, gamma-delta / immunology
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Receptors, Antigen, T-Cell, gamma-delta / metabolism*
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / pathology
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Th17 Cells / cytology
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Th17 Cells / immunology*
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Th17 Cells / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Tretinoin / pharmacology
Substances
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Antineoplastic Agents
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Homeodomain Proteins
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Il23a protein, mouse
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Integrins
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Interleukin-16
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Interleukin-23 Subunit p19
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RNA, Messenger
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Receptors, Antigen, T-Cell, gamma-delta
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Transforming Growth Factor beta
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integrin alpha4beta7
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RAG-1 protein
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Tretinoin