Blockade of NKG2D signaling prevents the development of murine CD4⁺T cell-mediated colitis

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.

DNA demethylation and histone H3K9 acetylation determine the active transcription of the NKG2D gene in human CD8+T and NK cells

“…46 Previous results had demonstrated that targeting the NKG2D-NKG2DL interaction might help prevent these pathologies. Blocking NKG2D with neutralizing anti-NKG2D monoclonal antibodies prevents the development of autoimmune diseases [47][48][49] and increases the survival of skin, bone marrow and cardiac allograft in animal models. 43,50,51 Therefore, modulation or downregulation of NKG2D by epigenetic mechanisms could be an additional therapeutic strategy for NKG2D blockage in these pathologies.…”

Involvement of an NKG2D Ligand H60c in Epidermal Dendritic T Cell-Mediated Wound Repair

“…Peroxidase-conjugated goat anti-rat IgG (H+L) (14-16-12) for Western blotting and Alexa Fluor 488 goat anti-rat IgG (H+L) (A11006) for immunostaining were from KPL (Gaithersburg, MD) and Invitrogen, respectively. A blocking anti-NKG2D mAb, HMG2D, was described previously (21).…”

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

“…4) that triggers through the associated YxxM motif-containing DAP10, has been proven to be of key importance in successful treatment of UC and CD. 143 Uncovering the molecular mechanisms of NKG2D signaling, the SCHOOL model suggests the cell is translated across the membrane into protein oligomerization in CYTO milieu, thus providing a general platform for receptor-mediated signaling (Fig. 5).…”