Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation. Front Immunol 2019;10:486
Date
04/03/2019Pubmed ID
30936879Pubmed Central ID
PMC6431666DOI
10.3389/fimmu.2019.00486Scopus ID
2-s2.0-85064229962 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
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.
Author List
Wang Z, Vaughan TY, Zhu W, Chen Y, Fu G, Medrzycki M, Nishio H, Bunting ST, Hankey-Giblin PA, Nusrat A, Parkos CA, Wang D, Wen R, Bunting KDAuthor
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAdoptive Transfer
Animals
CD8-Positive T-Lymphocytes
Colitis
Disease Models, Animal
Inflammatory Bowel Diseases
Intraepithelial Lymphocytes
Lipocalin-2
Lymphocyte Activation
Macrophage Activation
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Radiation Chimera
Rectal Prolapse
Signal Transduction
TOR Serine-Threonine Kinases