NF-κB/Atg5 Axis Linked to Treg Dysfunction in Kidney Antibody-Mediated Rejection

Antibody-mediated rejection (AMR) remains a leading cause of kidney allograft failure, and a new study in Cell Biology and Toxicology points to a mechanistic link between dysfunctional regulatory T cells and persistent macrophage-driven inflammation. The work, published open access on 8 October 2026, identifies Atg5-dependent regulation in Tregs as a key connection between adaptive immune dysfunction and innate immune activation during AMR, and proposes TNF-α/NF-κB signaling as a potential upstream mechanism.

The researchers report that AMR is characterized by reduced regulatory T cell (Treg) abundance together with increased accumulation of pro-inflammatory M1-like macrophages. Notably, both changes were attenuated by adoptive transfer of induced Tregs in the study’s experimental model, suggesting that restoring Treg activity can temper the macrophage inflammatory response that accompanies rejection.

Mechanistically, the study found that Atg5-dependent regulation is required for maintaining Treg-mediated immune control. Loss of Atg5 was associated with impaired autophagy-related signaling and enhanced inflammatory responses in macrophages, positioning this autophagy component as a hinge between Treg function and innate inflammation rather than a passive marker of cell stress.

The team also traced a possible upstream driver. TNF-α activated NF-κB signaling in Tregs, promoted enrichment of the p65 subunit at the Atg5 promoter, and was associated with reduced Atg5 expression and alterations in autophagy-associated markers. These effects were largely reversed by NF-κB inhibition, supporting a potential reciprocal interaction in which macrophage-associated inflammatory signaling impairs Treg regulation, which in turn feeds back on macrophage inflammation during AMR.

The authors caution that the mechanisms linking Treg dysfunction to persistent innate immune activation in AMR remain poorly defined, and the findings are presented as identifying a mechanistic link and a potential therapeutic direction rather than an established treatment. Preserving Treg autophagy-related function may represent a candidate strategy for AMR, but this preclinical evidence will require further validation before any clinical application.

Subject of Research: The role of the NF-κB/Atg5 axis in Treg regulation and macrophage inflammation during antibody-mediated rejection of kidney allografts.

Article Title: Targeting the NF-κB/Atg5 axis alleviates antibody-mediated rejection by preserving Atg5-dependent Treg regulation and limiting macrophage inflammation

Article References: Cheng, H., Ke, Z., Si, S., Zhu, Y., Yao, J., Zhang, G., Gui, Z., Chen, S., & Chen, M. (2026). Targeting the NF-κB/Atg5 axis alleviates antibody-mediated rejection by preserving Atg5-dependent Treg regulation and limiting macrophage inflammation. Cell Biology and Toxicology. https://doi.org/10.1007/s10565-026-10295-9

Image Credits: AI Generated

DOI: 10.1007/s10565-026-10295-9

Keywords: antibody-mediated rejection, kidney transplant, regulatory T cells, Atg5, autophagy, NF-κB, TNF-α, macrophages, M1 macrophages, transplant immunology, Targeting, axis