Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients

Abstract

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naïve T (T_Naïve ) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting T_Naïve cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4⁺ CD31⁺ ) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4⁺ CD31⁺ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57^- cell proliferation. In contrast, mDCs, but not IL-7, induced CD57⁺ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction. Trial Registration: ClinicalTrials.gov - NCT00565773.

Keywords: basic (laboratory) research/science; clinical research/practice; immunobiology; immunosuppressant - fusion proteins and monoclonal antibodies: alemtuzumab; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppression/immune modulation; immunosuppressive regimens - induction; kidney transplantation/nephrology; lymphocyte biology: differentiation/maturation; lymphocyte biology: proliferation.