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Indirect suppression of CD4 T cell activation through LAG-3-mediated trans-endocytosis of MHC class II.
Wakamatsu, Ei; Machiyama, Hiroaki; Toyota, Hiroko; Takeuchi, Arata; Hashimoto, Ryuji; Kozono, Haruo; Yokosuka, Tadashi.
Afiliación
  • Wakamatsu E; Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Electronic address: ewakama2@tokyo-med.ac.jp.
  • Machiyama H; Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
  • Toyota H; Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
  • Takeuchi A; Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
  • Hashimoto R; Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
  • Kozono H; Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba-shi, Chiba 263-8555, Japan.
  • Yokosuka T; Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. Electronic address: yokosuka@tokyo-med.ac.jp.
Cell Rep ; 43(9): 114655, 2024 Sep 24.
Article en En | MEDLINE | ID: mdl-39191259
ABSTRACT
Blockade of immune checkpoint receptors has shown outstanding efficacy for tumor immunotherapy. Promising treatment with anti-lymphocyte-activation gene-3 (LAG-3) has already been recognized as the next efficacious treatment, but there is still limited understanding of the mechanism of LAG-3-mediated immune suppression. Here, utilizing high-resolution molecular imaging, we find a mechanism of CD4 T cell suppression via LAG-3, in which LAG-3-bound major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) gather at the central region of an immunological synapse and are trans-endocytosed by T cell receptor-driven internalization motility toward CD4 and CD8 T cells expressing LAG-3. Downregulation of MHC class II molecules on APCs thus results in the attenuation of their antigen-presentation function and impairment of CD4 T cell activation. From these data, anti-LAG-3 treatment is suggested to have potency to directly block the inhibitory signaling via LAG-3 and simultaneously reduce MHC class II expression on APCs by LAG-3-mediated trans-endocytosis for recovery from T cell exhaustion.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Activación de Linfocitos / Linfocitos T CD4-Positivos / Antígenos de Histocompatibilidad Clase II / Antígenos CD / Proteína del Gen 3 de Activación de Linfocitos Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Activación de Linfocitos / Linfocitos T CD4-Positivos / Antígenos de Histocompatibilidad Clase II / Antígenos CD / Proteína del Gen 3 de Activación de Linfocitos Límite: Animals / Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos