TY - JOUR
T1 - Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation
AU - Wang, Zhengqi
AU - Vaughan, Tamisha Y.
AU - Zhu, Wandi
AU - Chen, Yuhong
AU - Fu, Guoping
AU - Medrzycki, Magdalena
AU - Nishio, Hikaru
AU - Bunting, Silvia T.
AU - Hankey-Giblin, Pamela A.
AU - Nusrat, Asma
AU - Parkos, Charles A.
AU - Wang, Demin
AU - Wen, Renren
AU - Bunting, Kevin D.
N1 - Publisher Copyright:
© 2019 Wang, Vaughan, Zhu, Chen, Fu, Medrzycki, Nishio, Bunting, Hankey-Giblin, Nusrat, Parkos, Wang, Wen and Bunting. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85064229962
UR - https://www.scopus.com/pages/publications/85064229962#tab=citedBy
U2 - 10.3389/fimmu.2019.00486
DO - 10.3389/fimmu.2019.00486
M3 - Article
C2 - 30936879
AN - SCOPUS:85064229962
SN - 1664-3224
VL - 10
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - MAR
M1 - 486
ER -