Impaired Direct Priming of CD8 T Cells by Donor-Derived Cytomegalovirus Following Kidney Transplantation

Abstract

Cytomegalovirus (CMV) infection increases the risk of complications after renal transplantation, but the mechanisms controlling donor-derived infection are not adequately characterized. Here, we assessed the risk of clinically significant CMV disease in donor-seropositive, recipient-seropositive (D+R+) renal transplantation and examined recipients' CMV antigen-specific cellular immune responses primed directly by donor cells. In a retrospective cohort of 569 patients administered standardized basiliximab-tacrolimus-mycophenolate-corticosteroid immunosuppressive therapy, CMV disease rates increased in D+R+ serostatus pairings compared with D2R+ pairings (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.36 to 5.01; P=0.004) and associated with increased donor-recipient HLA mismatch in the D+R+ group (HR [per class 1 mismatch], 1.43; 95% CI, 1.12 to 1.82]; P=0.02). D+R+ and D+R2 transplants in which the donor and recipient differentially expressed at least one HLA class I allele were followed prospectively from the time of transplantation. During the first year after transplantation, four of eight seropositive recipients and one of three seronegative recipients displayed peripheral blood CD8+ T cell responses to CMV presented by recipient-specific HLA. Notably, no recipients mounted responses to CMV presented by donorspecific HLA, despite the detection of CMV antigen expression in all seropositive donor organs examined (n=10), suggesting that the allograft of Class I HLA-mismatched seropositive donors is inaccessible to CD8+ T cell responses. Finally, pretransplant assays of anti-CMV cellular immunity predicted post-transplant CMV replication less accurately in D+R+ pairings than in D2R+ pairings, possibly reflecting in vitro assay specificity for recipient, rather than donor, HLA. These findings are relevant to the clinical management and immunologic understanding of donortransmitted viral infection.

Human CMV-specific T-cell responses in kidney transplantation; toward changing current risk-stratification paradigm

“…Both the CD8 + and CD4 + T‐cell compartments are crucial for controlling and restricting viral replication . Nevertheless, while it is suggested the preponderant role of CD8 + T cells for the control of hCMV replication , it appears that CD4 + T cells would be fundamental for conferring long‐lasting protection , either through the provision of T‐cell help in maintaining virus‐specific antibody responses and expanding the CD8 + T‐cell populations or by directly killing virus‐infected cells . A highly diverse virus‐specific T‐cell response develops between 4 and 6 weeks after primary antigen exposure.…”

“…To note, prediction of hCMV replication using different in vitro assays might potentially be misleading, especially among R+/D+, as hCMV peptides used as stimulators are presented by recipient HLA, thus in vivo viral presentation through donor cells could be underestimated .…”

The polyomavirus puzzle: is host immune response beneficial in controlling BK virus after adult hematopoietic cell transplantion?

“…These observations suggest a crucial role played by major histocompatability complex‐based viral recognition as uCB HCT often can allow greater degrees of HLA mismatching. Inadequate HLA matching likely results in poor presentation of viral epitopes to BKV‐specific CD8 + cytotoxic T cells and decreased viral clearance, as is demonstrated by cytomegalovirus infection in kidney transplantation patients . Furthermore, in kidney transplantation patients, greater degrees of HLA mismatching have been associated with increased incidences of BKV‐associated nephropathy .…”

CMV-infected kidney grafts drive the expansion of blood-borne CMV-specific T cells restricted by shared class I HLA molecules via presentation on donor cells

“…We previously reported donor CMV positivity as a risk factor of graft loss, especially in CMV-infected recipients (D+R+). 8 Also, CMV is commonly detected in transplanted kidneys from CMV-positive donors 9,10 and replication of CMV within kidney grafts is associated with a poor clinical outcome. 9,11 In addition, we showed that the deleterious effect of donor CMV positivity on kidney graft outcome was mainly observed in kidney transplant recipients with full HLA-I mismatch with their donors or with a strong post-transplant reduction in CD8 + T cell number.…”