Terminally differentiated effector memory T cells in kidney transplant recipients: New crossroads

Immunosenescence, the age-related dysregulation of innate and adaptive immunity, impairs immune response and increases inflammation, leading to higher infection and cardiovascular risks, particularly outside the field of transplantation. In kidney transplant recipients (KTRs), conditions like cytomegalovirus infection, old age, uremia, smoking, and diabetes, linked to poor outcomes, are associated with enhanced immunosenescence. Recent studies highlight the pathogenic role of cytotoxic T cells, particularly terminally differentiated effector memory T cells that reexpress CD45RA (T_EMRA), in graft dysfunction. A higher proportion of circulating CD8⁺ T_EMRA cells is observed in KTRs with chronic rejection. In antibody-mediated rejection, they invade the graft by superior chemotactic properties and binding to human leukocyte antigen (HLA) antibodies through FcγRIIIa (CD16). Also in microvascular inflammation without donor-specific antibodies, and even in patients without rejection but faster decline of kidney function, intragraft CD8⁺ T_EMRA cells were instrumental. CD8⁺ T_EMRA cells may explain the unresolved dismal graft outcomes associated with donor age and cytomegalovirus-serostatus mismatching and could become a novel therapeutic target in KTRs.