The Impact of T-cell Aging on Alloimmunity and Inflammaging

Abstract

Aging affects immunity broadly through changes caused by immunosenescence, clinically resulting in augmented susceptibility to infections, autoimmunity, and cancer. The most striking alterations associated with immunosenescence have been observed in the T-cell compartment with a significant shift toward a terminally differentiated memory phenotype taking on features of innate immune cells. At the same time, cellular senescence impairs T-cell activation, proliferation, and effector functions, compromising the effectiveness of immunity. In clinical transplantation, T-cell immunosenescence has been the main driver of less frequent acute rejections in older transplant recipients. This patient population, at the same time, suffers more frequently from the side effects of immunosuppressive therapy including higher rates of infections, malignancies, and chronic allograft failure. T-cell senescence has also been identified as an instigator of age-specific organ dysfunction through a process that has been coined “inflammaging,” accelerating organ injury and potentially contributing to the limited lifetime of organ transplants. Here, we provide a summary of the latest evidence on molecular characteristics of T-cell senescence affecting alloimmunity and organ quality while dissecting the consequences of unspecific organ injury and immunosuppression on T-cell senescence. Rather than conceptualizing immunosenescence as a broad and general “weaker” alloimmune response, it appears critical to understand both mechanisms and clinical effects in detail as a basis to refine treatment.

Editorial: Immunosenescence in organ transplantation

“…Hereby, dendritic cells were found as crucial drivers communicating augmented immunogenicity by promoting CD4 + T cells derived IL-17 production leading to compromised survival of older donor organs (4). Moreover, senescence of intragraft T cells has been characterized as an instigator of age-specific organ dysfunction through augmented SASP-related signaling accelerating organ injury and potentially contributing to the limited lifetime of organ transplants (5)(6)(7)(8)(9).…”

Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients

“…This type of immunesenescence results in a state of anergy that is readily broken with strong cytokine stimulation, such as would be seen with infections ( 121 ). Thus, while lower rates of acute graft rejection may be seen in STS transplant recipients, these recipients are at continued risk of chronic rejection ( 122 , 123 ).…”