Features of an exhausted T-cell compartment in kidney transplant patients
A.P. Bouvy, M. Klepper, M.M.L. Kho, M.G.H. Betjes, W. Weimar, C.C. Baan
Moderator(s): H.J.P.M. Koenen en H.G. Otten
Location(s): Breezaal
Category:
Introduction: T-cell exhaustion is a state of T-cell dysfunction which arises during persistent antigen stimulation, and is characterized by a hierarchical loss of T cell effector functions and a sustained expression of inhibitory receptors. We hypothesize that after kidney transplantation an exhausted T cell compartment is induced by donor antigen and that immunosuppressive therapy has different effects on this phenomenon.
Material and Methods: Patients (n=18) were treated with T-cell depleting rATG (6 mg/kg, n=9), or non-depleting, anti-CD25 antibody (basiliximab 2 x 40 mg, n=9) induction therapy, in combination with tacrolimus, MMF and steroids as maintenance therapy. Flow cytometry was used to determine T-cell exhaustion before and in the first year after transplantation by measuring proliferation in response to donor antigen and by the expression of the inhibitory molecules PD-1, TIM-3, LAG-3, CTLA4, CD160 and CD244 (2B4) on CD4+ and CD8+ naïve, central memory, effector memory and EMRA T-cells.
Results: In the first year after transplantation, a progressive decline in functionality of donor activated CD4+ and CD8+ memory T cells, but not of naïve T cells was found (p<0.05). For CD4+ T cells, only the CD4+ effector memory T cell population poorly responded upon donor antigen stimulation, while for the CD8+ T cells all memory T-cell subsets showed impaired proliferative responses (p<0.05). No differences were found between rATG and basiliximab treated patients. Next we measured whether the lack of anti-donor T-cell reactivity in the first year after transplantation is associated with a high expression pattern of the exhaustion markers PD-1, TIM-3, LAG-3, CTLA4, CD160 and CD244. For the exhaustion markers the highest expression levels were found on memory T cells, with increased percentages of PD-1, TIM3 and CD160 on CD4+ T cells (p<0.05) and increased percentages of CD160 and CD244 on CD8+ T cells (p<0.05).
Conclusion: Kidney transplant patients, regardless of their induction therapy, exhibit characteristics of T-cell exhaustion, reflected by a decreased proliferative capacity in response to donor antigen, which is accompanied by an increased expression of exhaustion markers.