Role for the Abi/wave protein complex in T cell receptor-mediated proliferation and cytoskeletal remodeling.
BACKGROUND
The molecular reorganization of signaling molecules after T cell receptor (TCR) activation is accompanied by polymerization of actin at the site of contact between a T cell and an antigen-presenting cell (APC), as well as extension of actin-rich lamellipodia around the APC. Actin polymerization is critical for the fidelity and efficiency of the T cell response to antigen. The ability of T cells to polymerize actin is critical for several steps in T cell activation including TCR clustering, mature immunological synapse formation, calcium flux, IL-2 production, and proliferation. Activation of the Rac GTPase has been linked to regulation of actin polymerization after TCR stimulation. However, the molecules required for TCR-mediated actin polymerization downstream of activated Rac have remained elusive. Here we identify a novel role for the Abi/Wave protein complex, which signals downstream of activated Rac, in the regulation of actin polymerization and T cell activation in response to TCR stimulation.


RESULTS
Here we show that Abi and Wave rapidly translocate from the T cell cytoplasm to the T cell:B cell contact site in the presence of antigen. Abi and Wave colocalize with actin at the T cell:B cell conjugation site. Moreover, Wave and Abi are necessary for actin polymerization after T cell activation, and loss of Abi proteins in mice impairs TCR-induced cell proliferation and IL-2 production in primary T cells. Significantly, the impairment in actin polymerization in cells lacking Abi proteins is due to the inability of Wave proteins to localize to the T cell:B cell contact site in the presence of antigen, rather than the destabilization of the components of the Wave protein complex.


CONCLUSIONS
The Abi/Wave complex is a novel regulator of TCR-mediated actin dynamics, IL-2 production, and proliferation.
Zipfel
Patricia A
PA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Bunnell
Stephen C
SC
Witherow
D Scott
DS
Gu
Jing Jin
JJ
Chislock
Elizabeth M
EM
Ring
Colleen
C
Pendergast
Ann Marie
AM
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D005110:Extracellular Space / Q000737:chemistry; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008954:Models, Biological; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000032:analysis / Q000502:physiology*
C513733:ABI1 protein, human; C513734:Abi1 protein, mouse; C490756:Abi2 protein, mouse; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; C114864:WASF1 protein, human; C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family