SLP-76 is required for optimal CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow.
Rapid arrest of T cells at target sites upon engagement of chemokine receptors is crucial to the proper functioning of the immune system. Although T-cell arrest always occurs under hydrodynamic forces in vivo, most studies investigating the molecular mechanisms of arrest have been performed under static conditions. While the requirement of the adapter protein SLP-76 (Src homology 2-domain containing leukocyte-specific phosphoprotein of 76 kDa) in TCR-induced integrin activation has been demonstrated, its role in chemokine-triggered T-cell adhesion is unknown. Using a flow chamber system, we show that SLP-76 plays an important role in regulating the transition from tethering and rolling to firm adhesion of T cells under physiological shear flow in response to CXCL12α (stromal cell-derived factor-1α); SLP-76-deficient primary T cells exhibited defective adhesion with a significant decrease in the number of firmly arrested cells. We further demonstrate the N-terminal phosphotyrosines of SLP-76 play a critical role in T-cell adhesion under flow. These findings reveal a novel role for SLP-76 in CXCR4-mediated T lymphocyte trafficking.
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Dooyoung
D
Lee
Jiyeon
J
Kim
Rebecca G
RG
Baker
Gary A
GA
Koretzky
Daniel A
DA
Hammer
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D006801:Humans; D019169:Jurkat Cells; D036904:Leukocyte Rolling / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D054387:Receptors, CXCR / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D054377:Chemokine CXCL12; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D054387:Receptors, CXCR; C092947:SLP-76 signal Transducing adaptor proteins; D019000:Phosphotyrosine