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<p>B7 costimulatory family member Butyrophilin 2A2 <b>(</b>BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increases murine CD4+Foxp3+ regulatory T cells (Treg) and reduces T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 therapy alleviates disease severity in murine nephrotoxic glomerulonephritis and autoimmune miscarriage while increasing Treg/Th17 ratios. Analyses of BTN2A2-deficient animals show exacerbation of disease associated with reduced Treg/Th17 ratios. BTN2A2 functions analogously on human T cells suppressing Th17, Th1 and Th2 responses while inducing Tregs. Together, our studies identify BTN2A2 as a modulator of CD45RO signaling in T cells, providing insight into how BTN2A2 regulates T cell-dependent immune responses including those mediating autoimmunity and transplant rejection.</p>

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Butyrophilin 2A2 promotes T cell immunoregulation via CD45 phosphatase activation and protects against murine autoimmune glomerulonephritis and pregnancy loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Shafat Ali,
  • Anders H. Berg,
  • Michifumi Yamashita,
  • Ambart E. Covarrubias,
  • Jordan Mundell,
  • Pranali N. Shah,
  • Ruan Zhang,
  • Vincent Dupont,
  • Bong-Ha Shin,
  • Shen Yang,
  • Madhusudhanarao Katiki,
  • Ramachandran Murali,
  • Margareta D. Pisarska,
  • Ravi Thadhani,
  • Peter S. Heeger,
  • Stanley C. Jordan,
  • S. Ananth Karumanchi

摘要

B7 costimulatory family member Butyrophilin 2A2 (BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increases murine CD4+Foxp3+ regulatory T cells (Treg) and reduces T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 therapy alleviates disease severity in murine nephrotoxic glomerulonephritis and autoimmune miscarriage while increasing Treg/Th17 ratios. Analyses of BTN2A2-deficient animals show exacerbation of disease associated with reduced Treg/Th17 ratios. BTN2A2 functions analogously on human T cells suppressing Th17, Th1 and Th2 responses while inducing Tregs. Together, our studies identify BTN2A2 as a modulator of CD45RO signaling in T cells, providing insight into how BTN2A2 regulates T cell-dependent immune responses including those mediating autoimmunity and transplant rejection.