Immune cell subsets in young kidney transplant recipients: Mechanistic and clinical perspectives

Kidney transplantation provides the best survival advantage for children, adolescents, and young adults with end-stage kidney disease, yet this group paradoxically experiences the poorest long-term graft survival. Immune-mediated rejection is the predominant cause, but the cellular mechanisms that underpin this age-related disparity remain incompletely defined. This review synthesises current evidence on the impact of immune ageing across adaptive and innate compartments, focusing on T cells, B cells, and natural killer (NK) cells. In younger recipients, a large naïve T- and B-cell pool, robust thymic output, and efficient germinal centre activity confer heightened alloimmune reactivity, driving increased risk of acute cellular and antibody-mediated rejection. In contrast, older recipients exhibit features of immunosenescence, including loss of CD28 expression, accumulation of terminally differentiated effector subsets, impaired germinal centre responses, and attenuated NK cytotoxicity, resulting in diminished capacity to mount de novo responses but greater vulnerability to infection. These immune trajectories have direct clinical implications: younger recipients may require intensified, mechanism-targeted immunosuppression, whereas older recipients may be more amenable to minimisation or tolerance protocols. We further highlight emerging evidence for premature immunosenescence in paediatric dialysis populations, the contribution of age-associated B cells and NK subsets, and the role of immunophenotype-guided therapeutic strategies. Current uniform immunosuppression protocols inadequately account for developmental and age-related immune heterogeneity. We argue for an age- and immune phenotype-informed approach to therapy, integrating longitudinal immune profiling, biomarker development, and systems immunology to improve risk stratification, promote tolerance, and ultimately extend allograft survival across all age groups.