Structural and Immunologic Reprogramming of Kidney Lymphatics in Chronic Transplant Rejection

A new study published in the Journal of Clinical Investigation has uncovered how human kidney lymphatics undergo profound structural remodeling and immunologic reprogramming during chronic allograft rejection—a revelation that could reshape our understanding of immune regulation and tissue injury in kidney transplantation.

Using a combination of 3D tissue imaging and single-cell RNA sequencing (scRNA-seq), researchers mapped the spatial architecture and molecular identity of lymphatic vessels in healthy and chronically rejecting kidney allografts. Their findings reveal that, far from being passive fluid conduits, lymphatic endothelial cells (LECs) in the kidney are actively involved in alloimmune responses—and may serve both as mediators of immune tolerance and targets of immune injury.

In healthy human kidneys, lymphatic capillaries are predominantly localized adjacent to cortical nephron segments and lack smooth muscle coverage, distinguishing them from collecting lymphatics in other organs. These capillaries express a unique molecular profile enriched for genes such as CCL14, DNASE1L3, and MDK, while showing low levels of classical immune-trafficking markers like LYVE1 and CXCL8.

This organ-specific identity was confirmed through multiorgan scRNA-seq comparisons encompassing over 13,000 LECs from kidney, skin, lung, intestine, and other tissues. Kidney-derived LECs clustered distinctly, suggesting specialized immunological functions and signaling dynamics.

In allografts with chronic mixed rejection—a combination of T cell– and antibody-mediated injury—this finely tuned lymphatic network becomes severely disorganized. Lymphatics invade the normally avascular medulla, lose their hierarchical architecture, and display a pathological shift in endothelial junction morphology from "button-like" gaps to "zipper-like" tight junctions, impairing their capacity to drain immune cells and tissue fluid.

These anatomical disruptions coincide with the appearance of tertiary lymphoid structures (TLSs)—ectopic immune aggregates rich in T and B cells—around and connected by the lymphatic vasculature. CD4+ T cells were found in close proximity to, and sometimes within, lymphatic lumens in rejecting kidneys, though their spatial distribution was more disorganized compared to healthy controls.

Strikingly, LECs in rejecting allografts express immunoregulatory molecules in response to local interferon-gamma (IFN-γ) signals, particularly from infiltrating T cells and NK cells. This includes upregulation of PVR (polio virus receptor) and LGALS9 (galectin-9), which engage inhibitory receptors on T cells like TIGIT and HAVCR2. These findings suggest an attempt at immune suppression by the lymphatics—possibly to counteract persistent inflammation.

Yet this tolerogenic reprogramming appears insufficient to shield LECs from immune-mediated damage. The study reports increased expression of HLA class II molecules (notably HLA-DR) on lymphatic endothelium and deposition of complement component C4d, consistent with direct alloantibody targeting. Genotyping confirmed that most lymphatics in rejecting allografts were of donor origin, underscoring their potential role as antigen-presenting targets.

This dual role of kidney lymphatics—as both regulators of immune tolerance and active participants in alloimmune injury—adds nuance to their emerging relevance in transplant immunobiology. The findings could help explain why lymphangiogenesis, long thought to promote graft acceptance by enhancing antigen drainage, has shown paradoxical associations with chronic rejection in both clinical and experimental studies.

By integrating transcriptomic profiling with spatial analysis, the study lays a foundation for future research aimed at therapeutically modulating lymphatic function. The authors propose that targeting lymphatic remodeling—perhaps by stabilizing junctional architecture or enhancing tolerogenic signaling—could prolong allograft survival.

However, limitations remain. The study is largely cross-sectional, and functional validation of the observed molecular signatures in vivo is needed. Moreover, the absence of lymphatic-targeted interventions in current transplant protocols signals a gap ripe for translational exploration.