SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms.
T cell activation through the T cell receptor (TCR) is subsequently modified by secondary signals that are either stimulatory or inhibitory. We show that CEACAM1 adhesion molecule isoforms containing a long cytoplasmic domain inhibited multiple T cell functions as a consequence of TCR ligation. Overexpression of CEACAM1 resulted in decreased proliferation, allogeneic reactivity, and cytokine production in vitro and delayed type hypersensitivity and inflammatory bowel disease in mouse models in vivo. Conditioned deletion of CEACAM1 in T cells caused increased TCR-CD3 complex signaling. This T cell regulation was dependent upon the presence of immunoreceptor tyrosine-based inhibition motifs (ITIM) within the cytoplasmic domain of CEACAM1 and the Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP1) in the T cell. Thus, CEACAM1 overexpression or deletion in T cells resulted in T cell inhibition or activation, respectively, revealing a role for CEACAM1 as a class of inhibitory receptors potentially amenable to therapeutic manipulation.
Nagaishi
Takashi
T
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Pao
Lily
L
Lin
Sue-Hwa
SH
Iijima
Hideki
H
Kaser
Arthur
A
Qiao
Shuo-Wang
SW
Chen
Zhangguo
Z
Glickman
Jonathan
J
Najjar
Sonia M
SM
Nakajima
Atsushi
A
Neel
Benjamin G
BG
Blumberg
Richard S
RS
D019264:Adoptive Transfer; D020816:Amino Acid Motifs; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000276:immunology*; D003092:Colitis / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000737:chemistry / Q000276:immunology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D020033:Protein Isoforms; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6