Characterization of eomesodermin and T-bet expression by allostimulated CD8+ T cells of healthy volunteers and kidney transplant patients in relation to graft outcome

Abstract

Abstract Memory T cell (Tmem) responses play a critical role in the outcome of allo-transplantation. While the role of the T-box transcription factor Eomesodermin (Eomes) in the maintenance of antigen-specific Tmem is well studied, little is known about Eomes+CD8+T cell responses after transplantation. We evaluated the phenotype and function of allo-reactive Eomes+CD8+T cells in healthy volunteers and kidney transplant patients and their relation to transplant outcome. High Eomes expression by steady-state CD8+T cells correlated with effector and memory phenotype. Following allo-stimulation, the expression of both the T-box proteins Eomes and T-bet by proliferating cells increased significantly, where high expression of Eomes and T-bet correlated with higher incidence of allo-stimulated IFNγ+TNFα+ CD8+T cells. In patients with no subsequent rejection, Eomes but not T-bet expression by donor-stimulated CD8+T cells, increased significantly after transplantation. This was characterized by increased EomeshiT-bet-/lo and decreased Eomes-/loT-bethi CD8+T cell subsets, with no significant changes in the EomeshiT-bethi CD8+T cell subset. No upregulation of exhaustion markers programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte-associated-antigen-4 (CTLA4) by donor-stimulated Eomes+CD8+T cells was observed. Before transplantation, in patients without rejection, there were higher incidences of EomeshiT-bet-/lo, and lower incidences of EomeshiT-bethi and Eomes-/loT-bethi donor-stimulated CD8+T cell subsets, compared to those with subsequent rejection. Overall, our findings indicate that high Eomes expression by allo-stimulated T-bet+CD8+T cells is associated with enhanced effector function, and that an elevated incidence of donor-stimulated CD8+T cells co-expressing high levels of Eomes and T-bet before transplantation, may correlate with an increased incidence of acute cellular rejection.