The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation.
BACKGROUND
The engagement of the T cell receptor results in actin cytoskeletal reorganization at the immune synapse (IS) and the triggering of biochemical signaling cascades leading to gene regulation and, ultimately, cellular activation. Recent studies have identified the WAVE family of proteins as critical mediators of Rac1-induced actin reorganization in other cell types. However, whether these proteins participate in actin reorganization at the IS or signaling pathways in T cells has not been investigated.


RESULTS
By using a combination of biochemical, genetic, and cell biology approaches, we provide evidence that WAVE2 is recruited to the IS, is biochemically modified, and is required for actin reorganization and beta-integrin-mediated adhesion after TCR crosslinking. Moreover, we show that WAVE2 regulates calcium entry at a point distal to PLCgamma1 activation and IP(3)-mediated store release.


CONCLUSIONS
These data reveal a role for WAVE2 in regulating multiple pathways leading to T cell activation. In particular, this work shows that WAVE2 is a key component of the actin regulatory machinery in T cells and that it also participates in linking intracellular calcium store depletion to calcium release-activated calcium (CRAC) channel activation.
Nolz
Jeffrey C
JC
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Gomez
Timothy S
TS
Zhu
Peimin
P
Li
Shuixing
S
Medeiros
Ricardo B
RB
Shimizu
Yoji
Y
Burkhardt
Janis K
JK
Freedman
Bruce D
BD
Billadeau
Daniel D
DD
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D005110:Extracellular Space / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D014158:Transcription, Genetic; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000502:physiology*
D015220:Calcium Channels; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D051966:Phospholipase C gamma; D002118:Calcium