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<p>Regulatory T cells (Tregs) are critical for immune tolerance. However, direct Treg therapies generate limited results. Recently, combinational treatment with Tregs and IL-2 to expand Tregs has become a hotspot and appeared to be promising. Here we unexpectedly find that infusion of CD4<sup>+</sup>CD25<sup>+</sup> Tregs plus IL-2 in lymphocyte-deficient mice causes skin and heart allograft rejection, while IL-2 or Treg alone does not. Depletion of CD25<sup>+</sup> Tregs in recipient mice receiving Tregs plus IL-2 abrogates allograft rejection. Gene profiling <i>via</i> qPCR arrays shows a tremendous increase in CXCL15 expression in allografts after the joint treatment. Its expression is augmented in Tregs from recipient mice. IL-2 augments CXCL15/IL-8 production by murine or human Tregs. Moreover, neutrophil infiltration is increased in allografts of mice receiving Tregs plus IL-2. However,&#xa0;allograft rejection or neutrophil infiltration does not occur when transferred Tregs lack CXCL15. Finally, the joint treatment provokes cardiac allograft rejection in pre-tolerized wild-type mice, while IL-2 or Treg alone does not. These results unveil hidden and detrimental effects of Tregs on transplant survival and somewhat challenge current dogma that Tregs are always immunosuppressive.</p>

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CD4+CD25+ regulatory T cells circumstantially initiate transplant rejection through CXCL15/neutrophil axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Feifei Qiu,
  • Huazhen Liu,
  • Chun-Ling Liang,
  • Yuchao Chen,
  • Nianqiao Gong,
  • Jonathan S. Bromberg,
  • Zhenhua Dai

摘要

Regulatory T cells (Tregs) are critical for immune tolerance. However, direct Treg therapies generate limited results. Recently, combinational treatment with Tregs and IL-2 to expand Tregs has become a hotspot and appeared to be promising. Here we unexpectedly find that infusion of CD4+CD25+ Tregs plus IL-2 in lymphocyte-deficient mice causes skin and heart allograft rejection, while IL-2 or Treg alone does not. Depletion of CD25+ Tregs in recipient mice receiving Tregs plus IL-2 abrogates allograft rejection. Gene profiling via qPCR arrays shows a tremendous increase in CXCL15 expression in allografts after the joint treatment. Its expression is augmented in Tregs from recipient mice. IL-2 augments CXCL15/IL-8 production by murine or human Tregs. Moreover, neutrophil infiltration is increased in allografts of mice receiving Tregs plus IL-2. However, allograft rejection or neutrophil infiltration does not occur when transferred Tregs lack CXCL15. Finally, the joint treatment provokes cardiac allograft rejection in pre-tolerized wild-type mice, while IL-2 or Treg alone does not. These results unveil hidden and detrimental effects of Tregs on transplant survival and somewhat challenge current dogma that Tregs are always immunosuppressive.