Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation

Zhengqi Wang, Tamisha Y. Vaughan, Wandi Zhu, Yuhong Chen, Guoping Fu, Magdalena Medrzycki, Hikaru Nishio, Silvia T. Bunting, Pamela Hankey Giblin, Asma Nusrat, Charles A. Parkos, Demin Wang, Renren Wen, Kevin D. Bunting

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number486
JournalFrontiers in immunology
Volume10
Issue numberMAR
DOIs
StatePublished - Jan 1 2019

Fingerprint

Colitis
Macrophages
T-Lymphocytes
Knockout Mice
Rectal Prolapse
Adoptive Transfer
Bone Marrow Transplantation
Phosphatidylinositol 3-Kinases
Inflammatory Bowel Diseases
Interleukin-2
Gastrointestinal Tract
Inflammation
Proteins

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Wang, Z., Vaughan, T. Y., Zhu, W., Chen, Y., Fu, G., Medrzycki, M., ... Bunting, K. D. (2019). Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation. Frontiers in immunology, 10(MAR), [486]. https://doi.org/10.3389/fimmu.2019.00486
Wang, Zhengqi ; Vaughan, Tamisha Y. ; Zhu, Wandi ; Chen, Yuhong ; Fu, Guoping ; Medrzycki, Magdalena ; Nishio, Hikaru ; Bunting, Silvia T. ; Giblin, Pamela Hankey ; Nusrat, Asma ; Parkos, Charles A. ; Wang, Demin ; Wen, Renren ; Bunting, Kevin D. / Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation. In: Frontiers in immunology. 2019 ; Vol. 10, No. MAR.
@article{a34d9b4e2ef24d66b31ef5b64e494d96,
title = "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.",
author = "Zhengqi Wang and Vaughan, {Tamisha Y.} and Wandi Zhu and Yuhong Chen and Guoping Fu and Magdalena Medrzycki and Hikaru Nishio and Bunting, {Silvia T.} and Giblin, {Pamela Hankey} and Asma Nusrat and Parkos, {Charles A.} and Demin Wang and Renren Wen and Bunting, {Kevin D.}",
year = "2019",
month = "1",
day = "1",
doi = "10.3389/fimmu.2019.00486",
language = "English (US)",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "MAR",

}

Wang, Z, Vaughan, TY, Zhu, W, Chen, Y, Fu, G, Medrzycki, M, Nishio, H, Bunting, ST, Giblin, PH, Nusrat, A, Parkos, CA, Wang, D, Wen, R & Bunting, KD 2019, 'Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation', Frontiers in immunology, vol. 10, no. MAR, 486. https://doi.org/10.3389/fimmu.2019.00486

Gab2 and Gab3 redundantly suppress colitis by modulating macrophage and CD8+ T-cell activation. / Wang, Zhengqi; Vaughan, Tamisha Y.; Zhu, Wandi; Chen, Yuhong; Fu, Guoping; Medrzycki, Magdalena; Nishio, Hikaru; Bunting, Silvia T.; Giblin, Pamela Hankey; Nusrat, Asma; Parkos, Charles A.; Wang, Demin; Wen, Renren; Bunting, Kevin D.

In: Frontiers in immunology, Vol. 10, No. MAR, 486, 01.01.2019.

Research output: Contribution to journalArticle

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 - Giblin, Pamela Hankey

AU - Nusrat, Asma

AU - Parkos, Charles A.

AU - Wang, Demin

AU - Wen, Renren

AU - Bunting, Kevin D.

PY - 2019/1/1

Y1 - 2019/1/1

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 - http://www.scopus.com/inward/record.url?scp=85064229962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064229962&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2019.00486

DO - 10.3389/fimmu.2019.00486

M3 - Article

C2 - 30936879

AN - SCOPUS:85064229962

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - MAR

M1 - 486

ER -