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Review
. 2025 May 1:16:1571828.
doi: 10.3389/fimmu.2025.1571828. eCollection 2025.

The effects of interleukin-21 in the biology of transplant rejection

Xiandong Zeng  1   2 , Yixiao Pan  1   2 , Qiang Xia  1   2 , Kang He  1   2
Affiliations
Review

The effects of interleukin-21 in the biology of transplant rejection

Xiandong Zeng et al. Front Immunol. .

Abstract

Interleukin-21 (IL-21) is a cytokine that plays a crucial role in regulating immune responses, affecting various immune cell types, including T cells, B cells, natural killer (NK) cells, and dendritic cells. IL-21 is primarily produced by CD4+ T cells, particularly follicular helper T (Tfh) cells and Th17 cells, and has been shown to be extensively involved in regulating both innate and adaptive immunity. IL-21 is particularly significant in the differentiation, proliferation, and effector functions of T cells and B cells. In the context of organ transplantation, IL-21 contributes to the promotion of acute transplant rejection and the development of chronic rejection, which is primarily antibody-mediated. This review summarizes relevant studies on IL-21 and discusses its multifaceted roles in transplant immune rejection, providing insights into therapeutic strategies for either inhibiting graft rejection or promoting tolerance. It also explores the feasibility of blocking the IL-21 signaling pathway within current immunosuppressive regimens, aiming to provide further clinical references.

Keywords: B lymphocyte; T lymphocyte; antibody-mediated rejection (AMR); interleukin-21 (IL-21); transplant rejection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
IL-21 affects a variety of immune cell effector functions, deeply involved in organ transplantation rejection. The Figure was created with www.biorender.com.
Figure 2
Figure 2
Pathways of Allogeneic Antigen Recognition and the Impact of IL-21 on DCs. From top to bottom, the figure shows the pathways of direct recognition, indirect recognition, and semi-direct recognition. On the one hand, IL-21 inhibits DC maturation by reducing the expression of surface co-stimulatory molecules such as CD86 and CD40 (not shown in the figure). On the other hand, IL-21 maintains the expression of CCR7 on DCs, enabling them to migrate to secondary lymphoid organs (SLOs). The figure was created with www.biorender.com.
Figure 3
Figure 3
IL-21 influences T cell lineage differentiation and effector functions. Since there is limited research on the effect of IL-21 on Th22 effector function, this subset will not be discussed here. The figure was created with www.biorender.com.
Figure 4
Figure 4
IL-21 promotes the formation and maintenance of germinal centers and plays a decisive role in the differentiation of GC-derived B cells into plasma cells. The CD40L-CD40 signaling pathway has been shown to work synergistically with IL-21 to promote Blimp-1 activation and plasma cell differentiation. CD40 signaling enhances STAT3-driven Blimp-1 upregulation by reducing Bcl-6 expression. Other co-stimulatory signals, such as ICOS-ICOSL and CD28-CD80/86, also promote plasma cell differentiation. Subsequently, DSA can injure endothelial cells by activating the complement system or through ADCC (antibody-dependent cellular cytotoxicity). In liver transplant patients experiencing AMR, hypertrophy of portal vein endothelial cells, obstructive portal vein disease, and microvasculitis are commonly observed. The drawing was inspired in part by Aldo J. Montano-Loza et al. (183). The figure was created with www.biorender.com.
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