title: T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice.
abstract: OBJECTIVE
  T helper (Th) 17 cells that express the retinoid-related orphan receptor (ROR) γt contribute to the development of colitis in mice, yet are found in normal and inflamed intestine. We investigated their development and functions in intestines of mice.
  
  
  METHODS
  We analyzed intestinal Th17 cells in healthy and inflamed intestinal tissues of mice. We analyzed expression of lymphotoxin (LT)α by Th17 cells and lymphoid tissue inducer-like cells.
  
  
  RESULTS
  LTα(-/-) and RORγt(-/-) mice had significantly lower percentages of naturally occurring Th17 cells in the small intestine than wild-type mice. Numbers of CD3(-)CD4(+/-)interleukin-7Rα(+)c-kit(+)CCR6(+)NKp46(-) lymphoid tissue inducer-like cells that produce interleukin-17A were increased in LTα(-/-) and LTα(-/-) × recombination activating gene (RAG)-2(-/-) mice, compared with wild-type mice, but were absent from RORγt(-/-) mice. Parabiosis of wild-type and LTα(-/-) mice and bone marrow transplant experiments revealed that LTα-dependent gut-associated lymphoid tissue structures are required for generation of naturally occurring Th17 cells. However, when wild-type or LTα(-/-) CD4(+)CD45RB(high) T cells were transferred to RAG-2(-/-) or LTα(-/-)×RAG-2(-/-) mice, all groups, irrespective of the presence or absence of LTα on the donor or recipient cells, developed colitis and generated Th1, Th17, and Th17/Th1 cells. RAG-2(-/-) mice that received a second round of transplantation, with colitogenic but not naturally occurring Th17 cells, developed intestinal inflammation. The presence of naturally occurring Th17 cells in the colons of mice inhibited development of colitis after transfer of CD4(+)CD45RB(high) T cells and increased the numbers of Foxp3(+) cells derived from CD4(+)CD45RB(high) T cells.
  
  
  CONCLUSIONS
  Gut-associated lymphoid tissue structures are required to generate naturally occurring Th17 cells that have regulatory activities in normal intestines of mice, but not for colitogenic Th17 and Th17/Th1 cells during inflammation.
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Yuichi
authors: Y
authors: Ono
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address: takagast@sc.itc.keio.ac.jp.
authors: Takanori
authors: T
authors: Kanai
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Tomohisa
authors: T
authors: Sujino
authors: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yasuhiro
authors: Y
authors: Nemoto
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Yasumasa
authors: Y
authors: Kanai
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Yohei
authors: Y
authors: Mikami
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Hayashi
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Atsuhiro
authors: A
authors: Matsumoto
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Hiromasa
authors: H
authors: Takaishi
authors: Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan.
authors: Haruhiko
authors: H
authors: Ogata
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Katsuyoshi
authors: K
authors: Matsuoka
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Tadakazu
authors: T
authors: Hisamatsu
authors: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Mamoru
authors: M
authors: Watanabe
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors: Toshifumi
authors: T
authors: Hibi
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000637:transplantation; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology*; D007421:Intestine, Small / Q000276:immunology; D007694:Killer Cells, Natural / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D010227:Parabiosis; D018417:Th1 Cells; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D017252:CD3 Complex; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D017493:Leukocyte Common Antigens; D008233:Lymphotoxin-alpha; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22; C498833:Foxp3 protein, mouse; C499308:Rag2 protein, mouse