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 D-R+ 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+R- 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 donor-specific 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 D-R+ 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 donor-transmitted viral infection.

Figure 1.

Development of CMV disease by donor-recipient risk based on serostatus combination. Data shown for first 12 months in light of few episodes of CMV disease beyond this point. VGC, valganciclovir.

Figure 2.

Influence of donor-recipient HLA mismatch on time to CMV disease in the D+R+ serostatus pairing. Data are shown for first 12 months in light of few episodes of CMV disease beyond this point.

Figure 3.

Assessment of recipient CD8+ cellular responses to HLA-specific CMV tetramers. CD8+ T cell responses against recipient-HLA-presented CMV-derived epitopes can be detected in both CMV-seropositive recipients of seropositive donor organs (D+R+) and CMV-negative recipients of seropositive organs (D+R−). (A) Gating strategy . (B) The upper row shows an example of a serial evaluation of the CD8+ T cell response to the HLA-A1 restricted epitope VTE (pp50) in the D+R+ setting at time of transplantation (d0), day 14, 3 months and 12 months after transplantation (top row). The lower row of B shows the T cell response to the HLA-A1 restricted epitope YSE (pp65) in a CMV-seronegative recipient of a CMV-seropositive donor organ, which was not evident early after transplantation, but then emerged and persisted through to 18 months after transplantation.

Figure 4.

HCMV immunostaining of implantation biopsy specimens from seropositive donor. (A) HCMV IE immunostaining. (B) HCMV LA immunostaining. (C) HCMV pp65 immunostaining.

Figure 5.

Cellular immunity and risk of CMV infection. The relationship between the IE-1 CD8+ response and the probability of CMV infection over the first post-transplant year, comparing D−R+ and D+R+ serostatus pairings.