Modulation of T cell-mediated Inflammation and Chemokine-induced Migration by an ABL-HEF1-Rap1 Signaling Axis

The identity of signaling mediators that link stimulation of chemokine receptors to pathways that promote T cell polarization and migration remains poorly understood. Chemokine signaling is essential for T lymphocyte trafficking during homeostasis and in response to inflammation. We have identified new roles for the Abl kinases in the regulation of chemokine-induced T cell migration (Figure 1) and polarization (Figure 2).

Fig. 1. Abl/Arg null T cells exhibit decreased migration on ICAM-coated surfaces in the presence of CCL21 compared to wild type cells.

Fig. 2. Abl  kinases are required for  chemokine-induced cell polarity.  Abl kinase Inhibitor (STI571) treated H9 human T cells or Abl/Arg null mouse primary T cells exhibit reduced polarization upon chemokine stimulation. Polarization was analyzed by staining the uropod with anti-ICAM-3 (human cells) or CD44 (mouse cells) antibodies.

We have uncovered a novel signaling network whereby Abl kinases, through the phosphorylation of the adaptor protein HEF1, modulate the activity of the Rap1 GTPase downstream of chemokine receptors (model Figure 3).

Moreover, we show for the first time that Abl kinases are required for T cell-mediated inflammation in mice. These findings highlight the potential clinical relevance of employing available small molecule inhibitors of the Abl kinases for treatment of T cell-mediated chronic inflammatory disorders. A role for the Abl-HEF1-Rap1 signaling module in the transmission of chemokine-induced signals required for T cell polarity, motility, and invasion may extend to cancer cells, as Abl kinases, HEF1 (NEDD9) and Rap1 have been independently implicated in the regulation of cancer cell invasion. Notably, inhibition of CXCR4 signaling is being tested for anti-metastasis therapy. Thus, disruption of chemokine-activated Abl-HEF1-Rap1 signaling with Abl kinase inhibitors may be exploited to effectively impair migration and invasion by both T cells and cancer cells. We have recently published these findings (Gu et al 2012 Science Signaling vol 5, issue 233 ra51). Several reviews of this work have been published (July 2012 Science Signaling vol. 5 issue 235 pe33; Nature Reviews Immunology September 2012, vol. 12).