NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant

Abstract

Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant (SOT) recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity allowing CMV reactivation is critical to guiding anti-viral therapy and examining CMV's impact on outcomes of SOT. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, non-viremic recipients. Subjects were sampled three-and twelve-months post-transplant, with additional samples oneweek and one-month post-viremia. Peripheral blood mononuclear cells (PBMC) were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 T cell transcriptomes were characterized by single-cell RNA-Seq. Pre-viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56 bright NK cells. Post-viremia, mature CD56 dim NK cells and CD28 -CD8 T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28 -CD8 T cells were associated with control of viremia. These findings suggest signatures of innate activation may be prognostic for CMV reactivation posttransplant, while CD8 T cell functionality is critical for effective control of CMV.

Differential IL-12 signaling induces human natural killer cell activating receptor-mediated ligand-specific expansion

“…Further analysis of IL-12 concentrations in the plasma of kidney transplant patients with reported NK cell expansion showed evidence for a long-term increase of the IL-12p40/IL-12p70 ratio in CMV PCR+ individuals, suggesting a contribution of these low IL-12 levels to NK cell expansion (Fig. 1 A; Pickering et al, 2021;Piazzolla et al, 2001;Ethuin et al, 2003). Consequently, we evaluated the efficacy of IL-12 to mediate human NK cell expansion directly by ex vivo stimulation of NK92 cells or purified primary NK cells with titrated amounts of IL-12 (Romee et al, 2012).…”

“…Low IL-12 concentrations lead to human primary NK cell activation without expansion Our objective was to evaluate the ability of IL-12 to mediate human NK cell proliferation and expansion since IL-12 is essential for mouse NK cell expansion and memory NK cell generation during MCMV infection (Sun et al, 2012). In line with the mouse model, phenotypic changes in human NK cells are associated with human CMV (HCMV) infection and elevated IL-15 levels in vivo (Pickering et al, 2021). Further analysis of IL-12 concentrations in the plasma of kidney transplant patients with reported NK cell expansion showed evidence for a long-term increase of the IL-12p40/IL-12p70 ratio in CMV PCR+ individuals, suggesting a contribution of these low IL-12 levels to NK cell expansion (Fig.…”

“…Kidney transplant recipients were enrolled after transplantation at Ronald Reagan Medical Center, and all patients gave informed consent. The University of California, Los Angeles Institutional Review Board approved this observational study (#11-001387; Pickering et al, 2021 ).…”

T‐lymphocyte subtyping: an early warning and a potential prognostic indicator of active cytomegalovirus infection in patients with sepsis

“…In addition, a recent study by Pickering et al . 14 found that NK cells and CD8 + T cells play an important role in the process of CMV infection in patients after renal transplantation and NK cells are closely related to the development of CMV infection while CD8 + T cells are essential for the control of CMV. Their results were consistent with our findings.…”

“…These conclusions are consistent with our research, as we found that the NK cell count, immunoglobulin G and the CD8 + CD28 + T-cell count in active CMV-infected patients with sepsis were significantly higher than in those without active CMV infection. In addition, a recent study by Pickering et al 14 found that NK cells and CD8 + T cells play an important role in the process of CMV infection in patients after renal transplantation and NK cells are closely related to the development of CMV infection while CD8 + T cells are essential for the control of CMV. Their results were consistent with our findings.…”