title: SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms.
abstract: 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.
authors.affiliation: Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagaishi
authors.forename: Lily
authors.initials: L
authors.lastname: Pao
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.forename: Shuo-Wang
authors.initials: SW
authors.lastname: Qiao
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glickman
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: 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
chemical_list: D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D020033:Protein Isoforms; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6