Reduced IL-7 Responsiveness Defined by Signal Transducer and Activator of Transcription 5 Phosphorylation in T Cells May Be a Marker for Increased Risk of Developing Cytomegalovirus Disease in Patients after Hematopoietic Stem Cell Transplantation

Abstract

Cytomegalovirus (CMV) reactivation may lead to CMV disease associated with high morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT); the identification of clinically relevant markers may aid in the identification of patients at increased risk for developing CMV-associated complications. We evaluated the phosphorylation of signal transducer and activator of transcription 5 (STAT5) in CD4(+) T cells, CD8(+) T cells, and TCRγδ T cells in response to stimulation with IL-7 or IL-2 after HSCT by analyzing blood samples taken monthly 1 to 6 months after HSCT. Patients were monitored weekly with a quantitative PCR from the time of engraftment for CMV viral load in whole blood until at least day 100 after HSCT. We identified a correlation between clinical outcome regarding CMV replication and the ability to respond to IL-7 and IL-2 defined by STAT5 phosphorylation (pSTAT5). Patients with recurrent or prolonged CMV replications had significantly lower pSTAT5 upon stimulation of T cells with either IL-7 or IL-2 at time points 1 through 3 than those without CMV replication (P < .05). This was also found after stimulation of CD8(+) T cells at time point 2 (P < .05). We conclude that reduced responses to IL-7, reflected by pSTAT5, may represent a clinically relevant functional biomarker for individuals at increased risk for CMV reactivation; our data may also aid in designing better strategies to improve anti-CMV immune responses without increasing the risk of developing graft-versus-host disease.

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation

“…Patients were routinely monitored for CMV reactivation with PCR and pre-emptively treated as described previously. 17 Antifungal, antibacterial and Pneumocystis jiroveci prophylaxis was given as previously described. 18 Serum analysis…”

Predictive biomarkers for cytomegalovirus reactivation before and after immunosuppressive therapy: A single-institution retrospective long-term analysis of patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic syndrome (DRESS)

“…Identifying biomarkers that predict the development of CMV reactivation could reduce its incidence and associated morbidity and mortality. There have been several reports on biomarkers or a panel of biomarkers with relevance for CMV reactivation in an immunosuppressive setting, such as graftversus-host disease (GVHD) and autoimmune diseases (Rieger et al, 2006;Poiret et al, 2014;Pérez-Bercoff et al, 2014;La Rosa et al, 2011;Limaye et al, 2016;van de Groep et al, 2018;Levine et al, 2012;Grant et al, 2012;Paczesny, 2013;Weigt et al, 2008); they included IL-7, IL-8, IL-10, IL-12, IL-23, tumor necrosis factor-α (TNF-α), interferon-g (IFN-g), and MIP-1α. However, no biomarkers previously reported can specifically and sensitively identify later development of CMV reactivation in these settings.…”

Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells

“…The importance of IL-7 and STAT5 signaling for CMV immunity in immunosuppressed patients has been suggested previously ( 90 ). Moreover, the recent use of JAK/STAT inhibitors for prevention of acute rejection in kidney transplant recipients has been associated with a significantly increased risk of CMV reactivation ( 91 ).…”