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Peer-reviewedCC BYCommunications Biology

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

  • Feifei Qiu1
  • Huazhen Liu1
  • Chun-Ling Liang1
  • Yuchao Chen1
  • Nianqiao Gong2
  • Jonathan S. Bromberg3
  • Zhenhua Dai1
  1. 1Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences
  2. 2Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
  3. 3Kidney and Pancreas Transplantation, Department of Microbiology & Immunology and Department of Surgery, University of Maryland School of Medicine
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{qiu2026cd4cd25,
  title = {{CD4+CD25+ regulatory T cells circumstantially initiate transplant rejection through CXCL15/neutrophil axis}},
  author = {Feifei Qiu and Huazhen Liu and Chun-Ling Liang and Yuchao Chen and Nianqiao Gong and Jonathan S. Bromberg and Zhenhua Dai},
  journal = {Communications Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s42003-026-10542-z},
  url = {https://doi.org/10.1038/s42003-026-10542-z},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - CD4+CD25+ regulatory T cells circumstantially initiate transplant rejection through CXCL15/neutrophil axis
AU  - Feifei Qiu
AU  - Huazhen Liu
AU  - Chun-Ling Liang
AU  - Yuchao Chen
AU  - Nianqiao Gong
AU  - Jonathan S. Bromberg
AU  - Zhenhua Dai
PY  - 2026
DA  - 2026/06/01
JO  - Communications Biology
DO  - 10.1038/s42003-026-10542-z
UR  - https://doi.org/10.1038/s42003-026-10542-z
AB  - 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.
SN  - 2399-3642
ER  -