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The Role of the Actin‐Binding Protein Cortactin in the Activation of T Cells: Implications for T‐Cell Acute Lymphoblastic Leukemia
Author(s) -
Martinez Ramon Castellanos,
Reyes Salvador Valle,
Schoor Michael
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02268
Subject(s) - cortactin , jurkat cells , biology , cd3 , microbiology and biotechnology , t cell , cell culture , xenotransplantation , cancer research , cell , immunology , cd8 , cytoskeleton , antigen , immune system , transplantation , medicine , genetics
T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive neoplasm due to high rates of organ infiltration and relapse, which are major obstacles for curing the disease. Infiltration of T‐ALL cells requires extravasation, a migratory process highly dependent on actin cytoskeleton dynamics. Cortactin is an actin‐binding protein that regulates actin remodeling and thus cell migration. Recently, we showed that cortactin overexpression in B‐cell ALL was correlated with infiltration, steroid treatment failure and relapse. However, it is unknown whether cortactin is expressed in leukemic T cells and what role it plays in T‐ALL biology. We analyzed cortactin expression in murine and human normal T cells and T‐ALL cell lines, and cortactin functions using different in vitro and in vivo methods such as transendothelial migration and xenotransplantation assays. We observed that the human leukemic T cell lines Jurkat, CEM and Molt‐3, as well as the leukemic murine T cell line 6645/4 expressed the 80 kDa WT isoform of cortactin. Importantly, all cell lines had significantly higher levels of cortactin than normal resting CD3 + cells. In addition, leukemic T cells transmigrated, infiltrated and colonized bone marrow organoids significantly more than normal T cells. Of note, in vivo xenotransplantation assays revealed that infiltrated leukemic T cells diminished cortactin expression suggesting that cortactin is needed for initial organ invasion, but not for subsequent functions within the organ. As leukemic cells display hyperactive TCR signaling, we examined cortactin and HS1 levels after activation of T cells. To this end, we used α‐CD3 and α‐CD28 to stimulate resting normal CD3 + cells and leukemic T cells, and found that in CD3 + , Jurkat and CEM cells, cortactin was up‐regulated during activation (~1000 fold‐over resting) in a time‐dependent manner, reaching a peak after full activation at 72 hours. Cortactin upregulation was also seen after phorbol 12‐myristate 13‐acetate and ionomycin stimulation in all cells. Importantly, levels of the hematopoietic homologue of cortactin, HS1, diminished as cortactin expression increased in CD3 + cells. Taken together, our results show that cortactin is overexpressed in leukemic T cells to endow them with enhanced migratory abilities. Cortactin is upregulated in both leukemic and normal T cells upon activation suggesting that cortactin might be an important protein for effector functions of activated T cells such as cytokine secretion.