Oncotarget

Research Papers:

CrkL is required for donor T cell migration to GvHD target organs

Nathan H. Roy, Mahinbanu Mammadli, Janis K. Burkhardt and Mobin Karimi _

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Oncotarget. 2020; 11:1505-1514. https://doi.org/10.18632/oncotarget.27509

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Abstract

Nathan H. Roy1, Mahinbanu Mammadli2, Janis K. Burkhardt1 and Mobin Karimi2

1 Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia Research Institute and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

2 Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA

Correspondence to:

Mobin Karimi,email: karimim@upstate.edu

Keywords: graft-versus-host disease; CrkL; T cell; migration; inflammation

Received: January 03, 2020     Accepted: February 17, 2020     Published: April 28, 2020

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.


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