Directing T cell traffic
Graft versus host disease (GVHD) is a life threatening complication that can occur in patients following allogeneic bone marrow transplantation and results from donor T cells infiltrating recipient tissues. T cell infiltration requires adhesion and migration; however, the pathways that mediate these processes are not fully understood. Yanping Huang and colleagues at the University of Pennsylvania determined that the adapter proteins CRK and CRKL regulate T cell adhesion, migration, and diapedesis. In murine models, CRK/CRKL-deficient T cells appropriately homed to lymphoid tissues; however, these cells did not traffic to sites of skin inflammation. In an allogeneic bone marrow (BM) transplantation model, mice that received BM in combination with CRK/CRKL-deficient T cells exhibited reduced GVHD compared to animals that received BM along with WT T cells. Importantly, animals that received BM with T cells lacking CRK and CRKL mounted an efficient graft verses leukemia response following challenge with host-type leukemia cells with minimal GVHD. Together, the results of this study demonstrate that CRK and CRKL regulate T cell trafficking and have potential to be therapeutically targeted to limit GVHD. The accompanying movie shows that WT T cells (video 1) are able to transmigrate through an endothelial monolayer, as indicated by the change in phase contrast from bright (red arrow) to dark (green arrow). CRK/CRKL-deficient T cells (video 2) are unable to transmigrate through the monolayer.
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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
Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)