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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis
1Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Abstract:
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.
Insights
The NKG2D receptor is crucial in T cell-mediated inflammatory bowel diseases. Blocking NKG2D signaling effectively reduced colitis in mice, suggesting it as a potential therapeutic target.
Area of Science:
- Immunology
- Gastroenterology
Background:
- NKG2D is an activating receptor on immune cells responding to cellular stress.
- Its role in T cell-mediated intestinal inflammation is not fully understood.
Purpose of the Study:
- To investigate the role of NKG2D signaling in CD4(+) T cell-mediated colitis.
- To evaluate NKG2D as a therapeutic target for inflammatory bowel diseases.
Main Methods:
- Induction of colitis in SCID mice via adoptive transfer of CD4(+)CD45RB(high) T cells.
- Analysis of NKG2D and its ligands on immune cells in the lamina propria.
- Treatment with anti-NKG2D monoclonal antibody (MAb) to assess therapeutic effects.
Main Results:
- Colitic mice showed increased CD4(+)NKG2D(+) T cells and NKG2D ligand expression on dendritic cells.
- Anti-NKG2D MAb treatment suppressed colitis, reduced leukocyte infiltration, and decreased IFN-gamma production.
- NKG2D signaling is critically involved in CD4(+) T cell-driven disease progression.
Conclusions:
- NKG2D pathway plays a significant role in the pathogenesis of inflammatory bowel diseases.
- Targeting NKG2D offers a promising therapeutic strategy for inflammatory bowel diseases.
