Increased Frequency of BK Virus-Specific Polyfunctional CD8+ T Cells Predict Successful Control of BK Viremia After Kidney Transplantation

Abstract

Background BK virus infection remains an important cause of loss of allograft function after kidney transplantation. We sought to determine whether polyfunctional T cells secreting multiple cytokines simultaneously, which have been shown to be associated with viral control, could be detected early after start of BK viremia, which would provide insight into the mechanism of successful antiviral control. Methods Peripheral blood mononuclear cells collected during episodes of BK viral replication were evaluated by multiparameter flow cytometry after stimulation by overlapping peptide pools of BK virus antigen to determine frequency of CD8+ and CD4+ T cells expressing 1 or more cytokines simultaneously, as well as markers of T cell activation, exhaustion, and maturation. Results BK virus controllers, defined as those with episodes of BK viremia of 3 months or less, had an 11-fold increase in frequency of CD8+ polyfunctional T cells expressing multiple cytokines, as compared with patients with prolonged episodes of BK viremia. Patients with only low level BK viremia expressed low frequencies of polyfunctional T cells. Polyfunctional T cells were predominantly of the effector memory maturation subtype and expressed the cytotoxicity marker CD107a. Conclusions Noninvasive techniques for immune assessment of peripheral blood can provide insight into the mechanism of control of BK virus replication and may allow for future patient risk stratification and customization of immune suppression at the onset of BK viremia. 5

BK Virus Nephropathy: Histological Evolution by Sequential Pathology

“…A more effective antiviral cellular response may explain improved SV40T tissue‐clearance rates and amelioration of the activity of tubular destruction when interstitial mononuclear cells were present. The concept of an ultimately beneficial mononuclear cell response in BKVAN is supported by other studies of antiviral inflammation . The causal relationship between inflammatory cells and parenchymal tubular damage appeared to be bidirectional and complex.…”

“…Antigen‐specific T cells can recognize nonstructural (small t and large T) antigenic targets and virus capsid proteins (VP1, VP2, and VP3) . In early BK viremia, circulating CD4 + T helper and T cytotoxic cells and specific polyfunctional CD8 + T cells are detectable. Virus‐specific lymphocyte clones infiltrate into infected kidneys, classified by next‐generation sequencing of TCRs following ex vivo BK or allospecific HLA peptide stimulation .…”

“…Persistent high‐level viremia was a powerful risk factor, increasing graft loss fivefold. Other studies have linked specific cellular responses to BK peptides and expansion of cytotoxic CD8 + T cells or polyfunctional CD4 T cells with viral control and outcome. A more effective antiviral cellular response may explain improved SV40T tissue‐clearance rates and amelioration of the activity of tubular destruction when interstitial mononuclear cells were present.…”

BK Polyomavirus: Clinical Aspects, Immune Regulation, and Emerging Therapies

“…It has been demonstrated that in KTRs, reconstitution of BKV-specific T cells is associated with better control of viruria and viremia (8,71,(77)(78)(79)(80)(81). These studies indicate that immune control is dependent on both CD4 ϩ and CD8 ϩ T cells (82) and correlates with the frequency of polyfunctional BKV-specific T cells (83). This suggests that monitoring the frequency of BKV-specific T cells following transplantation may provide a strategy to predict the risk of viral reactivation and BKVAN, as shown previously for T cell responses to human cytomegalovirus (CMV) in transplant recipients (84).…”

<p>BK virus in transplant recipients: current perspectives</p>

“…24 Patients with more polyfunctional CD8+ T cells expressing multiple cytokines were more likely to clear BK infections within 3 months. 25 Bohl et al studied urine samples from 20 recipient pairs of a deceased kidney transplant. Each of these pairs received 2 kidneys from the same deceased donor.…”