Allogeneic CD4 T Cells sustain effective BK Polyomavirus-specific CD8 T-Cell response in kidney transplant recipients

Introduction BK polyomavirus-associated nephropathy (BKPyVAN) is a significant complication in kidney transplant recipients, associated with a higher level of plasmatic BK polyomavirus (BKPyV) replication and leading to poor graft survival. Methods We prospectively followed 100 kidney transplant recipients with various degrees of BKPyV reactivation (no BKPyV reactivation, BKPyV-DNAuria, BKPyV-DNAemia, and biopsy-proven BKPyVAN (bp-BKPyVAN), 25 patients per group) and evaluated BKPyV-specific T-cell functionality and phenotype. Results We demonstrate that bp-BKPyVAN is associated with a loss of BKPyV-specific T-cell proliferation, cytokine secretion, and cytotoxic capacities. This severe functional impairment is associated with an overexpression of lymphocyte inhibitory receptors (PD1, CTLA4, TIGIT, and TIM3), highlighting an exhausted-like phenotype of BKPyV-specific CD4 and CD8 T cells in bp-BKPyVAN. This T cell dysfunction is associated with low class II donor-recipient HLA divergence. By contrast, in the context of higher class II donor-recipient HLA divergence, allogeneic CD4 T cells can provide help that sustains BKPyV-specific CD8 T-cell responses. In vitro, allogeneic HLA-mismatched CD4 T cells rescue BKPyV-specific CD8 T-cell responses. Conclusion Our findings suggest that in kidney transplant recipients, allogeneic CD4 T cells can help to maintain an effective BKPyV-specific CD8 T-cell response that better controls BKPyV replication in the kidney allograft and may protect against BKPyVAN.