BKPyV-specific T-cell Exhaustion in Kidney Transplant Recipients: Targeting Inhibitory Receptors Improves Their Functionality

Background. BK polyomavirus (BKPyV) nephropathy is a significant complication of kidney transplantation associated with high levels of BKPyV replication in plasma and poor graft survival. It is currently treated by reducing immunosuppression to restore the immune response. Methods. We analyzed circulating T cells from 28 kidney transplant recipients with detectable levels of BKPyV DNA in the blood (BKPyV DNAemia). Immunosuppression was significantly reduced in all these patients. We evaluated BKPyV-specific T-cell functionality and phenotype and assessed graft outcomes prospectively. Results. BKPyV DNAemia was rapidly controlled in 13 patients (controllers [C] group), whereas viral replication was sustained in the other 15, who were considered not to have responded to reduced immunosuppression (noncontroller [NC] group). The induction and maintenance therapies used were similar in the C and NC groups. The slope of renal function decline tended to be worse in the NC group than in the C group ( P < 0.055). BKPyV-specific T-cell functions (T-cell proliferation and cytokine secretion) were weaker in the NC group than in the C group. This functional impairment was associated with an overexpression of several inhibitory receptors (programmed cell death protein 1 [PD1], T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, or T-cell immunoglobulin and mucin-containing protein 3 [TIM3]), highlighting an exhausted-like phenotype of BKPyV-specific CD4 and CD8 T cells in the NC group. T-cell inhibition was not overcome by a single blocking antibody against inhibitory receptors, whereas a combination of anti-PD1 and anti-TIM3 antibodies significantly restored BKPyV-specific CD8 T-cell functions ( P < 0.05). Conclusions. Sustained BKPyV DNAemia was associated with an exhausted phenotype of BKPyV-specific T cells despite immunosuppression reduction in kidney transplant recipients. We show that anti-BKPyV-specific CD8 functions can be restored ex vivo by blocking the PD1 and TIM3 pathways, paving the way for new treatment strategies.