A lysosomal protein negatively regulates surface T cell antigen receptor expression by promoting CD3zeta-chain degradation.
Modulation of surface T cell antigen receptor (TCR) expression is an important mechanism for the regulation of immune responses and the prevention of T cell hyperactivation and autoimmunity. The TCR is rapidly internalized after antigen stimulation and then degraded in lysosomes. However, few of the molecules involved in this process have been identified. We demonstrate that the lysosomal protein LAPTM5 negatively regulated surface TCR expression by specifically interacting with the invariant signal-transducing CD3zeta chain and promoting its degradation without affecting other CD3 proteins, CD3epsilon, CD3delta, or CD3gamma. TCR downmodulation required the polyproline-tyrosine motifs and the ubiquitin-interacting motif of LAPTM5. LAPTM5 deficiency resulted in elevated TCR expression on both CD4(+)CD8(+) thymocytes and spleen T cells after CD3 stimulation, as well as enhanced T cell responses in vitro and in vivo. These results identify a lysosomal protein important for CD3zeta degradation and illustrate a unique mechanism for the control of surface TCR expression and T cell activation.
Ouchida
Rika
R
Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
Yamasaki
Sho
S
Hikida
Masaki
M
Masuda
Keiji
K
Kawamura
Kiyoko
K
Wada
Akihiko
A
Mochizuki
Shigenobu
S
Tagawa
Masatoshi
M
Sakamoto
Akemi
A
Hatano
Masahiko
M
Tokuhisa
Takeshi
T
Koseki
Haruhiko
H
Saito
Takashi
T
Kurosaki
Tomohiro
T
Wang
Ji-Yang
JY
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017874:Immediate-Early Proteins / Q000276:immunology / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D017874:Immediate-Early Proteins; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C018589:lysosomal proteins