Abstract
The success of cancer therapies based on allogeneic hematopoietic stem cell transplant relies on the ability to separate graft-versus-host disease (GvHD) from graft-versus-tumor (GVT) responses. Controlling donor T cell migration into peripheral tissues is a viable option to limit unwanted tissue damage, but a lack of specific targets limits progress on this front. Here, we show that the adaptor protein CrkL, but not the closely related family members CrkI or CrkII, is a crucial regulator of T cell migration. In vitro, CrkL-deficient T cells fail to polymerize actin in response to the integrin ligand ICAM-1, resulting in defective migration. Using a mouse model of GvHD/GVT, we found that while CrkL-deficient T cells can efficiently eliminate hematopoietic tumors they are unable to migrate into inflamed organs, such as the liver and small intestine, and thus do not cause GvHD. These results suggest a specific role for CrkL in trafficking to peripheral organs but not the lymphatic system. In line with this, we found that although CrkL-deficient T cells could clear hematopoietic tumors, they failed to clear the same tumor growing subcutaneously, highlighting the role of CrkL in controlling T cell migration into peripheral tissues. Our results define a unique role for CrkL in controlling T cell migration, and suggest that CrkL function could be therapeutically targeted to enhance the efficacy of immunotherapies involving allogeneic donor cells.
Highlights
T cell migration out of the vasculature into peripheral tissue is a key control point in the inflammatory response
Quantitation of the total F-actin signal confirmed that DKO and CrkL KO T cells responding to Intercellular Adhesion Molecule 1 (ICAM-1) contained significantly less F-actin than WT or CrkI/II KO T cells (Figure 1C)
We showed previously that T cells lacking all CT10 Regulator of Kinase (Crk) family proteins exhibit defective migration into inflamed tissue in vivo, and an inability to carry out transendothelial migration (TEM) in vitro [8]
Summary
T cell migration out of the vasculature into peripheral tissue is a key control point in the inflammatory response. T cell recruitment is highly regulated by the local endothelial cells which, in response to pro-inflammatory cues, up-regulate molecules such as chemokines and adhesion receptors. These molecules promote T cell adhesion to the endothelial monolayer, and guide migration through the monolayer into the tissue [1]. The endothelial ligands ICAM-1 and VCAM-1 are recognized by the T cell integrins LFA-1 and VLA4, respectively, which mediate firm adhesion to the vascular wall and subsequent migration into inflamed tissue [1, 2]. In addition to acting as adhesion receptors, integrins initiate downstream signaling events that are important for T cell migration. Disruption of signaling events downstream of engaged integrins could yield more context-specific therapies, but to develop such strategies, a better understanding of the relevant signaling pathways is required
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