Proteomics screening post pediatric allogeneic hematopoietic stem cell transplantation reveals an association between increased expression of inhibitory receptor FCRL6 on γδ T cells and CMV reactivation

Objective To study kinetics and associations between inflammation related proteins in circulation after pediatric allogenic hematopoietic stem cell transplantation (HSCT) to reveal proteomic signatures or individual soluble proteins associated with specific complications post HSCT. Methods We used a proteomics method called Proximity Extension Assay to repeatedly measure 180 different proteins together with clinical variables, cellular immune reconstitution, and blood viral copy numbers in 27 children aged 1-18 years during a two-year follow up after allogenic HSCT. Protein profile analysis was done using unsupervised hierarchical clustering and a regression-based method, while Bonferroni-corrected Mann-Whitney U test was used for time point specific comparison of individual proteins against outcome. Results At 6 months after allogenic HSCT, we could identify a protein profile pattern associated with occurrence of the complications chronic graft-versus-host disease, viral infections, relapse, and death. When protein markers were analyzed separately, the plasma concentration of the inhibitory and cytotoxic T cell surface protein FCRL6 (Fc receptor-like 6) was higher in patients with CMV viremia (log2-fold change 1.5 (p0.00099), 2.5 (p=0.00035) and 2.2 (p=0.045) at time points 6, 12 and 24 months). Flow cytometry confirmed that FCRL6 expression was higher in innate-like γδ T cells, indicating that these cells have a role in controlling CMV reactivation in HSCT recipients. Conclusions The potentially druggable FCRL6 receptor on cytotoxic T cells appears to have a role in controlling CMV viremia post-HSCT. Our results suggest that system level analysis is a useful addition to the studying of single biomarkers in allogeneic HSCT.