Proteomics screening after pediatric allogenic hematopoietic stem cell transplantation reveals an association between increased expression of inhibitory receptor FCRL6 on γδ T cells and cytomegalovirus reactivation

Immunol Cell Biol. 2024 Jul;102(6):513-525. doi: 10.1111/imcb.12762. Epub 2024 May 10.

Abstract

We studied the associations between inflammation-related proteins in circulation and complications after pediatric allogenic hematopoietic stem cell transplantation (HSCT), to reveal proteomic signatures or individual soluble proteins associated with specific complications after HSCT. 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 (1-18 years of age) during a 2-year follow-up after allogenic HSCT. Protein profile analysis was performed using unsupervised hierarchical clustering and a regression-based method, while the Bonferroni-corrected Mann-Whitney U-test was used for time point-specific comparison of individual proteins against outcome. At 6 months after allogenic HSCT, we could identify a protein profile pattern associated with occurrence of the complications such as 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 cytomegalovirus (CMV) viremia [log2-fold change 1.5 (P = 0.00099), 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 are involved in controlling CMV reactivation in HSCT recipients. In conclusion, the potentially druggable FCRL6 receptor on cytotoxic T cells appears to have a role in controlling CMV viremia after HSCT. Furthermore, our results suggest that system-level analysis is a useful addition to the studying of single biomarkers in allogenic HSCT.

Keywords: FCRL6; HSCT; biomarkers; gd T cells; pediatric; proteomics; γδ T cells.

MeSH terms

  • Adolescent
  • Biomarkers
  • Child
  • Child, Preschool
  • Cytomegalovirus Infections* / immunology
  • Cytomegalovirus* / immunology
  • Cytomegalovirus* / physiology
  • Female
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / immunology
  • Hematopoietic Stem Cell Transplantation* / adverse effects
  • Humans
  • Infant
  • Male
  • Proteomics* / methods
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Receptors, Fc / metabolism
  • Transplantation, Homologous*
  • Virus Activation*

Substances

  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, Fc
  • Biomarkers