Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Lung inflammatory injury and tissue repair (Jul 2023)
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
CRK proteins selectively regulate T cell migration into inflamed tissues
Yanping Huang, … , Taku Kambayashi, Janis K. Burkhardt
Yanping Huang, … , Taku Kambayashi, Janis K. Burkhardt
Published January 26, 2015
Citation Information: J Clin Invest. 2015;125(3):1019-1032. https://doi.org/10.1172/JCI77278.
View: Text | PDF
Research Article Immunology

CRK proteins selectively regulate T cell migration into inflamed tissues

  • Text
  • PDF
Abstract

Effector T cell migration into inflamed sites greatly exacerbates tissue destruction and disease severity in inflammatory diseases, including graft-versus-host disease (GVHD). T cell migration into such sites depends heavily on regulated adhesion and migration, but the signaling pathways that coordinate these functions downstream of chemokine receptors are largely unknown. Using conditional knockout mice, we found that T cells lacking the adaptor proteins CRK and CRK-like (CRKL) exhibit reduced integrin-dependent adhesion, chemotaxis, and diapedesis. Moreover, these two closely related proteins exhibited substantial functional redundancy, as ectopic expression of either protein rescued defects in T cells lacking both CRK and CRKL. We determined that CRK proteins coordinate with the RAP guanine nucleotide exchange factor C3G and the adhesion docking molecule CASL to activate the integrin regulatory GTPase RAP1. CRK proteins were required for effector T cell trafficking into sites of inflammation, but not for migration to lymphoid organs. In a murine bone marrow transplantation model, the differential migration of CRK/CRKL-deficient T cells resulted in efficient graft-versus-leukemia responses with minimal GVHD. Together, the results from our studies show that CRK family proteins selectively regulate T cell adhesion and migration at effector sites and suggest that these proteins have potential as therapeutic targets for preventing GVHD.

Authors

Yanping Huang, Fiona Clarke, Mobin Karimi, Nathan H. Roy, Edward K. Williamson, Mariko Okumura, Kazuhiro Mochizuki, Emily J.H. Chen, Tae-Ju Park, Gudrun F. Debes, Yi Zhang, Tom Curran, Taku Kambayashi, Janis K. Burkhardt

×

Figure 1

Crk and Crkl are deleted in T cells of CRK/CRKL Dko mice.

Options: View larger image (or click on image) Download as PowerPoint

Crk and Crkl are deleted in T cells of CRK/CRKL Dko mice.
(A) CD4+ T ce...
(A) CD4+ T cells were purified from lymph nodes of CRK/CRKL Dko and WT mice. Preactivated T cells were prepared by stimulating with plate-bound anti-CD3 and anti-CD28 for 2 days and culturing without stimuli for an additional 5 days. Whole cell lysates were analyzed by SDS-PAGE and immunoblotted with anti-CRKL, anti-CRK, and anti-ZAP70. (B) (C) Preactivated CD4+ T cells made as in A were fixed and permeabilized, and the intracellular staining of CRK (B) and CRKL (C) was determined by flow cytometry. (D) Thymus, spleens, and lymph nodes (LNs) were isolated from WT and CRK/CRKL Dko mice. Single-cell suspensions were analyzed by flow cytometry using the indicated antibodies. (E) Gated CD4+ and CD8+ T cells from lymph nodes (mixed peripheral and mesenteric lymph nodes) were analyzed for the indicated surface markers.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts