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

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.