Crk adaptor proteins include three family members: CrkI and CrkII are from the alternatively spliced crk gene, and CrkL is from the crk-like gene. These ubiquitously expressed proteins play important roles in multiple signaling pathways. However, their functions in T cells are poorly characterized, partly because germline-deficiency for Crk or CrkL leads to lethality in mice. By breeding Crkflox/flox:CrkLflox/flox mice to CD4Cre mice, we generated mice conditionally deficient for both Crk and CrkL in mature T cells. These mice are viable and fertile. We find that T cells lacking both Crk and CrkL develop normally, but are defective in chemotactic responses to multiple chemokines. Further analysis revealed that while Rac1 activation is intact, Rap1 activation is perturbed, as is tyrosine phosphorylation of the Rap1 GEF C3G. Consistent with this, these cells exhibit reduced chemokine-stimulated adhesion to ICAM-1 and fibronectin, and defective diapedesis. Using a cutaneous DTH model, we show that Crk and CrkL are required for efficient T cell migration to sites of inflammation. In addition to regulating T cell migration, Crk proteins also control T cell activation. Double deficient T cells showed significant proliferative defects upon allogeneic antigen stimulation. These results demonstrate a key role for Crk proteins in T cell function. We are currently working on defining Crk/CrkL-dependent pathways and analyzing functions of Crk proteins in singly deficient T cells.
- Copyright © 2013 by The American Association of Immunologists, Inc.