Cytoskeletal protein 4.1R negatively regulates T-cell activation by inhibiting the phosphorylation of LAT.
Protein 4.1R (4.1R) was first identified in red cells where it plays an important role in maintaining mechanical stability of red cell membrane. 4.1R has also been shown to be expressed in T cells, but its function has been unclear. In the present study, we use 4.1R-deficient mice to explore the role of 4.1R in T cells. We show that 4.1R is recruited to the immunologic synapse after T cell-antigen receptor (TCR) stimulation. We show further that CD4+ T cells of 4.1R-/- mice are hyperactivated and that they displayed hyperproliferation and increased production of interleukin-2 (IL-2) and interferon gamma (IFNgamma). The hyperactivation results from enhanced phosphorylation of LAT and its downstream signaling molecule ERK. The 4.1R exerts its effect by binding directly to LAT, and thereby inhibiting its phosphorylation by ZAP-70. Moreover, mice deficient in 4.1R display an elevated humoral response to immunization with T cell-dependent antigen. Thus, we have defined a hitherto unrecognized role for 4.1R in negatively regulating T-cell activation by modulating intracellular signal transduction.
Kang
Qiaozhen
Q
Red Cell Physiology Laboratory, New York Blood Center, New York, NY 10065, USA.
Yu
Yu
Y
Pei
Xinhong
X
Hughes
Richard
R
Heck
Susanne
S
Zhang
Xihui
X
Guo
Xinhua
X
Halverson
Gregory
G
Mohandas
Narla
N
An
Xiuli
X
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C514956:Epb41 protein, mouse; D007376:Interleukin-2; C491734:Lat protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D007371:Interferon-gamma; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3