Vav links the T cell antigen receptor to the actin cytoskeleton and T cell activation independently of intrinsic Guanine nucleotide exchange activity.
BACKGROUND
T cell receptor (TCR) engagement leads to formation of signaling microclusters and induction of rapid and dynamic changes in the actin cytoskeleton, although the exact mechanism by which the TCR initiates actin polymerization is incompletely understood. The Vav family of guanine nucleotide exchange factors (GEF) has been implicated in generation of TCR signals and immune synapse formation, however, it is currently not known if Vav's GEF activity is required in T cell activation by the TCR in general, and in actin polymerization downstream of the TCR in particular.


RESULTS
Here, we report that Vav1 assembles into signaling microclusters at TCR contact sites and is critical for TCR-initiated actin polymerization. Surprisingly, Vav1 functions in TCR signaling and Ca(++) mobilization via a mechanism that does not appear to strictly depend on the intrinsic GEF activity.


CONCLUSIONS
We propose here a model in which Vav functions primarily as a tyrosine phosphorylated linker-protein for TCR activation of T cells. Our results indicate that, contrary to expectations based on previously published studies including from our own laboratory, pharmacological inhibition of Vav1's intrinsic GEF activity may not be an effective strategy for T cell-directed immunosuppressive therapy.
Miletic
Ana V
AV
Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, St Louis, MO, USA.
Graham
Daniel B
DB
Sakata-Sogawa
Kumiko
K
Hiroshima
Michio
M
Hamann
Michael J
MJ
Cemerski
Saso
S
Kloeppel
Tracie
T
Billadeau
Daniel D
DD
Kanagawa
Osami
O
Tokunaga
Makio
M
Swat
Wojciech
W
D000199:Actins / Q000502:physiology*; D000818:Animals; D001704:Biopolymers / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D000199:Actins; D001704:Biopolymers; D020662:Guanine Nucleotide Exchange Factors; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse