Mass cytometry reveals single-cell kinetics of cytotoxic lymphocyte evolution in CMV-infected renal transplant patients

Abstract

Cytomegalovirus (CMV) infection is associated with graft rejection in renal transplantation. Memory-like natural killer (NK) cells expressing NKG2C and lacking FcεRIγ are established during CMV infection. Additionally, CD8+ T cells expressing NKG2C have been observed in some CMV-seropositive patients. However, in vivo kinetics detailing the development and differentiation of these lymphocyte subsets during CMV infection remain limited. Here, we interrogated the in vivo kinetics of lymphocytes in CMV-infected renal transplant patients using longitudinal samples compared with those of nonviremic (NV) patients. Recipient CMV-seropositive (R+) patients had preexisting memory-like NK cells (NKG2C+CD57+FcεRIγ–) at baseline, which decreased in the periphery immediately after transplantation in both viremic and NV patients. We identified a subset of prememory-like NK cells (NKG2C+CD57+FcεRIγlow–dim) that increased during viremia in R+ viremic patients. These cells showed a higher cytotoxic profile than preexisting memory-like NK cells with transient up-regulation of FcεRIγ and Ki67 expression at the acute phase, with the subsequent accumulation of new memory-like NK cells at later phases of viremia. Furthermore, cytotoxic NKG2C+CD8+ T cells and γδ T cells significantly increased in viremic patients but not in NV patients. These three different cytotoxic cells combinatorially responded to viremia, showing a relatively early response in R+ viremic patients compared with recipient CMV-seronegative viremic patients. All viremic patients, except one, overcame viremia and did not experience graft rejection. These data provide insights into the in vivo dynamics and interplay of cytotoxic lymphocytes responding to CMV viremia, which are potentially linked with control of CMV viremia to prevent graft rejection.

NK- and T-cell granzyme B and K expression correlates with age, CMV infection and influenza vaccine-induced antibody titres in older adults

“…The prevalence of chronic CMV infection in most countries increases with age ( Fowler et al, 2022 ) and is best known for the inflationary effect it has on the T-cell compartment, particularly in driving clonality in CD8 + T-cells, resulting in an increase in subsets exhibiting an exhausted, senescent-like phenotype, while potentially exacerbating a reduction of the overall pool of naïve subsets ( Nikolich-Žugich, 2018 ). Evidence from experimental models ( Fehniger et al, 2007 ) and longitudinal studies ( van Leeuwen et al, 2004 ; Ishiyama et al, 2022 ; Vaaben et al, 2022 ) indicates that CMV is an important determinant of the abundance of GZB+ NK-cell and CD8 + and γδ T-cells, in line with our own findings. However, ours appears to be the first documentation of the cell-specific patterns of GZK expression in older adults, although a previous study showed that serum levels of GZK increase with CMV infection ( Bade et al, 2005 ).…”

“…Although the sample of young adults was relatively small, the MFI of GZB for CD4 + and CD8 + T-cells was also significantly higher in CMV-positive participants (standardized β [95% CI]: CD4 = 1.27 [.002, 2.534], CD8 = 1.38 [.42, 2.33]). Finally, since CMV infection and reactivation have been shown to drive perforin expression in NK- and CD8 + T-cells, respectively ( Pietersma et al, 2010 ; Ishiyama et al, 2022 ), and perforin is a critical mediator of the cytolytic response of those cells ( McElhaney et al, 2020 ), we also investigated whether the aforementioned associations between CMV and GZB/GZK+ cell frequency were dependent on perforin expression. There was a tendency for the associations between CMV seropositivity and GZB+ CD8 + and Vδ1+ cells or GZK+ CD4 + and CD8 + cells to be stronger for the perforin positive vs. negative subsets ( Supplementary Figure S1A ), which was similarly present when considering the ratio of perforin positive to negative cells within each cell population ( Supplementary Figure S1B ).…”

CMV reactivation initiates long-term expansion and differentiation of the NK cell repertoire

“…The nature of HSCT transplant conditioning and donor choice is likely to impact substantially on the profile of NK reconstitution and similar findings have been seen after umbilical donor transplantion ( 22 )although an increase in NK number was not seen in the setting of haploidential transplantation ( 25 , 26 ). In the renal transplant setting a recent study has revealed a similar finding of increased number and frequency of NK cells after HCMV reactivation ( 27 ).…”

System Analysis Based on Lipid-Metabolism-Related Genes Identifies AGT as a Novel Therapy Target for Gastric Cancer with Neoadjuvant Chemotherapy

“…Interestingly, the PI3K/AKT signaling pathway was remarkably enriched ( Figure 7 D). The PI3K/AKT pathway has been demonstrated to be involved in the EMT of several types of human cancer [ 33 , 34 , 35 , 36 ]. To explore whether PI3K/AKT signaling was involved in AGT-mediated EMT, we examined the effect of AGT on the activation of PI3K/AKT.…”