Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis.
It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8(+) T cells, and gammadelta T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells is characterized by significant increase of CD4(+)NKG2D(+) T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c(+) dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4(+)CD45RB(high) T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-gamma by lamina propria CD4(+) T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4(+) T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases.
Ito
Y
Y
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Kanai
T
T
Totsuka
T
T
Okamoto
R
R
Tsuchiya
K
K
Nemoto
Y
Y
Yoshioka
A
A
Tomita
T
T
Nagaishi
T
T
Sakamoto
N
N
Sakanishi
T
T
Okumura
K
K
Yagita
H
H
Watanabe
M
M
D019264:Adoptive Transfer; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D002352:Carrier Proteins / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C468260:UL16 binding protein 1, mouse; C114735:minor H antigen H60; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse