Clin Transplant Res.  2024 Dec;38(4):326-340. 10.4285/ctr.24.0057.

Belatacept and regulatory T cells in transplantation: synergistic strategies for immune tolerance and graft survival

• Kim GR
• Nam KH
• Choi JM

• KMID: 2563954
• DOI: http://doi.org/10.4285/ctr.24.0057

Abstract

Calcineurin inhibitors (CNIs) have been a cornerstone in solid organ transplantation for many years; however, their prolonged use is linked to significant adverse effects, most notably nephrotoxicity. Belatacept, a modified version of cytotoxic T lymphocyte antigen-4 immunoglobulin with increased binding affinity for its ligand, has emerged as a viable alternative to traditional CNIs due to its lower toxicity profile. Despite these benefits, belatacept is associated with a higher rate of acute rejection, which presents a challenge for long-term graft survival. This review reevaluates the limitations of belatacept in achieving long-term acceptance of transplants and highlights the importance of regulatory T (Treg) cells in maintaining immune tolerance and preventing graft rejection. Additionally, it discusses the potential benefits of combining therapies that boost Treg cells with belatacept to increase the effectiveness of immunosuppression and improve graft outcomes.

Keyword

Abatacept; Transplantation; Regulatory T cells

Figure

• 

  Fig. 1 Historical overview of belatacept development. A historical overview of the understanding of belatacept development from 1991 to 2024 is provided. CTLA-4, cytotoxic T lymphocyte antigen-4; Ig, immunoglobulin; BENEFIT, Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression. Diagram created with BioRender.

• 

  Fig. 2 CD28 signaling in FOXP3 expression and the effects of belatacept. CD28 costimulatory signaling is essential for the induction and maintenance of FOXP3 by activating the PI3K-AKT-mTOR and RelA/NFκB signaling pathways. RelA binds to the FOXP3 promoter region to induce FOXP3 expression, whereas the PI3K pathway regulates chromatin remodeling to enhance FOXP3 expression. FOXP3 is the key transcription factor in Treg cells, promoting the expression of suppressive functional markers such as CD25, CTLA-4, IL-10, TGF-β, CD39 and CD73, which collectively suppress alloreactive conventional T cells. However, belatacept blocks this CD28 signaling pathway by inhibiting CD28 binding to CD80/86 on APCs, thereby reducing FOXP3 expression. APC, antigen-presenting cell; MHC, major histocompatibility complex; Treg, regulatory T; TCR, T cell receptor; mTOR, mammalian target of rapamycin; CTLA-4, cytotoxic T lymphocyte antigen-4; IL, interleukin; TGF, transforming growth factor. Diagram created with BioRender.

• 

  Fig. 3 Perspectives on therapeutic strategies for transplantation. Belatacept binds to CD80/86 on APCs, inhibiting the activation of alloreactive effector T cells by blocking CD28 signaling. However, it also inhibits CD28 signaling in Treg cells, impairing their differentiation and maintenance, and it cannot regulate CD28-negative T cells. Strategies that increase Treg cells, such as low-dose IL-2, can restore Treg cells inhibited by belatacept and effectively inhibit not only alloreactive effector T cells but also CD28-negative effector T cells. Combining belatacept with drugs that enhance Treg cells can effectively prevent graft rejection and maintain immune tolerance. Treg, regulatory T; TCR, T cell receptor; MHC, major histocompatibility complex; APC, antigen-presenting cell; IL, interleukin; IFN, interferon; CTLA-4, cytotoxic T lymphocyte antigen-4. Diagram created with BioRender.

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