Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice

Takayuki Tomita, Takanori Kanai, Yasuhiro Nemoto, Toshimitsu Fujii, Kengo Nozaki, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Naoya Sakamoto, Teruji Totsuka, Mamoru Watanabe

Research output: Contribution to journalArticle

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Abstract

Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4+ T cells continuously recirculate in peripheral blood during the chronic phase of colitis. Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4+CD45RBhigh cells into SCID mice in combination with a parabiosis system. Results: In colitic SCID recipients, first, almost all CD4+ CD45RBhigh donor cells were converted to CD4+CD44highCD62L- IL-7Rα high effector-memory T (TEM) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow. Second, SCID mice retransferred with the colitic peripheral blood CD4+ T cells developed colitis that is identical to the original colitis. Third, CD4+ cells in parabionts between established colitic RAG-2-/- mice induced by adoptive transfer of Ly5.1+ or Ly5.2+ CD4+CD45RBhigh T cells were well mixed in almost equal proportions at various sites 2 weeks after parabiosis surgery, and the redistribution of Ly5.1+ and Ly5.2+ CD4+ T cells was significantly suppressed in FTY720-treated parabionts. Conclusions: Together, these findings indicate that colitogenic CD4+ TEM cells continuously recirculate in established colitic mice, suggesting that therapeutic approaches targeting systemic CD4+ TEM cells, such as bone marrow transplantation, rather than those targeting only intestinal CD4+ T cells, may be feasible for the treatment of IBD.

Original languageEnglish
Pages (from-to)1630-1640
Number of pages11
JournalInflammatory Bowel Diseases
Volume14
Issue number12
DOIs
Publication statusPublished - 2008

Fingerprint

T-Lymphocytes
Colitis
Parabiosis
SCID Mice
Adoptive Transfer
Inflammatory Bowel Diseases
Leukapheresis
Thoracic Duct
Blood Circulation
Bone Marrow Transplantation
Mucous Membrane
Therapeutics
Spleen
Lymph Nodes
Bone Marrow
Tissue Donors

Keywords

  • Colitis
  • Colitogenic memory T cells
  • FTY720
  • Parabiosis
  • Recirculation

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Tomita, T., Kanai, T., Nemoto, Y., Fujii, T., Nozaki, K., Okamoto, R., ... Watanabe, M. (2008). Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice. Inflammatory Bowel Diseases, 14(12), 1630-1640. https://doi.org/10.1002/ibd.20636

Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice. / Tomita, Takayuki; Kanai, Takanori; Nemoto, Yasuhiro; Fujii, Toshimitsu; Nozaki, Kengo; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Sakamoto, Naoya; Totsuka, Teruji; Watanabe, Mamoru.

In: Inflammatory Bowel Diseases, Vol. 14, No. 12, 2008, p. 1630-1640.

Research output: Contribution to journalArticle

Tomita, T, Kanai, T, Nemoto, Y, Fujii, T, Nozaki, K, Okamoto, R, Tsuchiya, K, Nakamura, T, Sakamoto, N, Totsuka, T & Watanabe, M 2008, 'Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice', Inflammatory Bowel Diseases, vol. 14, no. 12, pp. 1630-1640. https://doi.org/10.1002/ibd.20636
Tomita, Takayuki ; Kanai, Takanori ; Nemoto, Yasuhiro ; Fujii, Toshimitsu ; Nozaki, Kengo ; Okamoto, Ryuichi ; Tsuchiya, Kiichiro ; Nakamura, Tetsuya ; Sakamoto, Naoya ; Totsuka, Teruji ; Watanabe, Mamoru. / Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice. In: Inflammatory Bowel Diseases. 2008 ; Vol. 14, No. 12. pp. 1630-1640.
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AU - Tomita, Takayuki

AU - Kanai, Takanori

AU - Nemoto, Yasuhiro

AU - Fujii, Toshimitsu

AU - Nozaki, Kengo

AU - Okamoto, Ryuichi

AU - Tsuchiya, Kiichiro

AU - Nakamura, Tetsuya

AU - Sakamoto, Naoya

AU - Totsuka, Teruji

AU - Watanabe, Mamoru

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AB - Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4+ T cells continuously recirculate in peripheral blood during the chronic phase of colitis. Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4+CD45RBhigh cells into SCID mice in combination with a parabiosis system. Results: In colitic SCID recipients, first, almost all CD4+ CD45RBhigh donor cells were converted to CD4+CD44highCD62L- IL-7Rα high effector-memory T (TEM) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow. Second, SCID mice retransferred with the colitic peripheral blood CD4+ T cells developed colitis that is identical to the original colitis. Third, CD4+ cells in parabionts between established colitic RAG-2-/- mice induced by adoptive transfer of Ly5.1+ or Ly5.2+ CD4+CD45RBhigh T cells were well mixed in almost equal proportions at various sites 2 weeks after parabiosis surgery, and the redistribution of Ly5.1+ and Ly5.2+ CD4+ T cells was significantly suppressed in FTY720-treated parabionts. Conclusions: Together, these findings indicate that colitogenic CD4+ TEM cells continuously recirculate in established colitic mice, suggesting that therapeutic approaches targeting systemic CD4+ TEM cells, such as bone marrow transplantation, rather than those targeting only intestinal CD4+ T cells, may be feasible for the treatment of IBD.

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