*Purpose: Rejection remains an obstacle to overcome after transplantation. IL-21 is the most potent stimulators of driving GC B cells into plasma cells. Basic researches about the role of IL-21 in immune status after transplantation are limited. A higher level of IL-21 in patients with stable status after transplantation was observed by Luminex assay, which triggered our interests in studying the function of IL-21 in kidney transplantation.

*Methods: Luminex assay was used to analyze the cytokine signature and antibody class-switching level in patients with no rejection (NR)(n=30), TCMR (n=28), and ABMR (n=8). Then, a rodent kidney transplantation model was established with injected exogenous IL-21 to mimic the serum IL-21 level in stable patients. The histopathology evaluation, cytokine levels, and lymphocytes were analyzed to illuminate the mechanism of allograft rejection.

*Results: A distinct cytokine signature in patients with active rejection was found. The IL-21 level in NR cohort was significantly higher than both TCMR (P <0.001) and ABMR (P =0.005) cohorts. An enhanced antibody class switching rate was observed in both rejection cohorts, TCMR and ABMR. In contrast, exogenous IL-21 administration accelerated the active rejection after KT. Further analysis revealed that the increase of IL-21 in spleen induced proliferation of CD4+ T cells and CD19+ cells after IL-21 treatment.

*Conclusions: IL-21 plays a critical role in active rejection after kidney transplantation, that could be a potential therapy target of active rejection.

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