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Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1
Hideki Iijima1, Markus F Neurath, Takashi Nagaishi
1Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Abstract:
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule that has been proposed to negatively regulate T cell function. We have shown that CEACAM1 is associated with specific regulation of T helper cell (Th)1 pathways, T-bet-mediated Th1 cytokine signaling, and Th1-mediated immunopathology in vivo. Mice treated with anti-mouse CEACAM1-specific monoclonal antibody (mAb) CC1 during the effector phase exhibited a reduced severity of trinitrobenzene sulfonic acid colitis in association with decreased interferon (IFN)-gamma production. Although oxazolone colitis has been reported as Th2 mediated, mice treated with the CC1 mAb or a CEACAM1-Fc chimeric protein exhibited a reduced severity of colitis in association with a significant reduction of IFN-gamma and T-bet activation, whereas signal transducer and activator of antigen 4 activation was unaffected. Both interleukin-4 and IFN-gamma gene-deficient mice exhibited less severe colitis induction by oxazolone. Direct ligation of T cells in vitro with the murine hepatitis virus spike protein, a natural ligand for the N-domain of CEACAM1, inhibited the differentiation of naive cells into Th1 but not Th2 cells and activation of Th1 but not Th2 cytokine production. These results indicate that CEACAM1 isoforms are a novel class of activation-induced cell surface molecules on T cells that function in the specific regulation of Th1-mediated inflammation such as that associated with inflammatory bowel disease.
Insights
Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) regulates T helper 1 (Th1) cell responses. Targeting CEACAM1 reduces Th1-mediated inflammation, offering potential therapeutic strategies for inflammatory bowel disease.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1) is a cell surface molecule implicated in T cell regulation.
- CEACAM1's specific role in T helper cell (Th)1 pathways and associated immunopathology requires further elucidation.
Purpose of the Study:
- To investigate the function of CEACAM1 in regulating Th1-mediated inflammation in vivo and in vitro.
- To determine the therapeutic potential of targeting CEACAM1 in models of inflammatory bowel disease.
Main Methods:
- Treatment of mice with anti-CEACAM1 monoclonal antibody (mAb) CC1 or CEACAM1-Fc chimeric protein in trinitrobenzene sulfonic acid and oxazolone colitis models.
- Analysis of cytokine production (e.g., interferon-gamma) and transcription factor activation (e.g., T-bet).
- In vitro studies involving T cell ligation with murine hepatitis virus spike protein.
Main Results:
- Anti-CEACAM1 treatment reduced colitis severity and decreased interferon-gamma production in both models.
- CEACAM1 blockade significantly reduced T-bet activation without affecting signal transducer and activator of transcription 4.
- In vitro, CEACAM1 ligation inhibited Th1 differentiation and cytokine production but not Th2 responses.
Conclusions:
- CEACAM1 isoforms are novel, activation-induced cell surface molecules on T cells.
- CEACAM1 specifically regulates Th1-mediated inflammation, including inflammatory bowel disease.
- Targeting CEACAM1 presents a potential therapeutic strategy for Th1-driven inflammatory conditions.
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