Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 208, Issue 12, Pages 2545-2560Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20110853
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Funding
- Cell Dynamics Research Center [2011-0001159]
- Ministry for Health, Welfare and Family Affairs [A100159, A090252]
- National Research Foundation [20110030157]
- BioImaging Research Center at Gwangju Institute of Science and Technology
- Grants-in-Aid for Scientific Research [23310135] Funding Source: KAKEN
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Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8(+) T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) zeta-chain and enhances TCR signaling by enhancing zeta-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR zeta-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell-APC interaction.
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