Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation

Abstract

Inflammatory Bowel Disease (IBD) is a multi-factorial chronic inflammation of the gastrointestinal tract prognostically linked to CD8+ T-cells, but little is known about their mechanism of activation during initiation of colitis. Here, Grb2-associated binding 2/3 adaptor protein double knockout mice (Gab2/3−/−) were generated. Gab2/3−/− mice, but not single knockout mice, developed spontaneous colitis. To analyze the cellular mechanism, reciprocal bone marrow (BM) transplantation demonstrated a Gab2/3−/− hematopoietic disease-initiating process. Adoptive transfer showed individual roles for macrophages and T-cells in promoting colitis development in vivo. In spontaneous disease, intestinal intraepithelial CD8+ but much fewer CD4+, T-cells from Gab2/3−/− mice with rectal prolapse were more proliferative. To analyze the molecular mechanism, reduced PI3-kinase/Akt/mTORC1 was observed in macrophages and T-cells, with interleukin (IL)-2 stimulated T-cells showing increased pSTAT5. These results illustrate the importance of Gab2/3 collectively in signaling responses required to control macrophage and CD8+ T-cell activation and suppress chronic colitis.

A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice

“… 31 The main contribution to colitis development was mediated by cytokine producing, proliferative, CTLs in the intraepithelial compartment of mice. 32 Amuc_1100 significantly decreased the proportion of CTLs in the spleen and the colonic infiltration of CTLs. Moreover, Amuc_1100 inhibited the activation of CTLs through the upregulation of PD-1.…”

“…CTLs are emerging as major mediators of human IBD, which is also prognostically linked to CTL profiling 31. The main contribution to colitis development was mediated by cytokine producing, proliferative, CTLs in the intraepithelial compartment of mice 32. Amuc_1100 significantly decreased the proportion of CTLs in the spleen and the colonic infiltration of CTLs.…”

Roles of Macrophages in the Development and Treatment of Gut Inflammation

“…Li et al found the central role of alternative M2 skewing of miR-155 in colitis and suggested that macrophages might be the main target of treatment ( Li et al, 2018 ). The Grb2-associated binding protein 2 (Gab2), which plays a role in regulating the activation of macrophages and T cells, and Grb2-associated binding protein 3 (Gab3), which is highly expressed in some immune cell types, redundantly regulate the activation of macrophages and CD8 + T cells to inhibit colitis ( Uno et al, 2010 ; Bezman et al, 2012 ; Best et al, 2013 ; Festuccia et al, 2014 ; Kaneda et al, 2016 ; Wang et al, 2019 ; Ma et al, 2020b ). Human catestatin (hCT), which has immunomodulatory properties, can reduce the severity of inflammatory recurrence by regulating M1 macrophages and releasing pro-inflammatory cytokines ( Zhang et al, 2009 ; Rabbi et al, 2017 ).…”

Identification of microRNA-16-5p and microRNA-21-5p in feces as potential noninvasive biomarkers for inflammatory bowel disease

“…Besides, GRB2 makes a great difference in the progression of autoimmune diseases due to its involvement in T cells’ development [ 57 ]. GRB2 associated binding protein 2/3 (Gab2/3) double knockout mice could develop spontaneous colitis with rectal prolapse and diarrhea, mainly involving macrophages and CD8 + T cells, which was due to the role of Gab2/3 in suppressing the inactivation of immune cells in the process of inflammation [ 58 ]. SUZ12 was reported to be an oncogene in colorectal cancer, which plays a cancer-promoting role by methylating histone H3 [ 59 ].…”