Robust Identification of Suitable T-Cell Subsets for Personalized CMV-Specific T-Cell Immunotherapy Using CD45RA and CD62L Microbeads

• Published in: International journal of molecular sciences 2019-03, Vol.20 (6), p.1415
• Main Authors: Mangare, Caroline, Tischer-Zimmermann, Sabine, Riese, Sebastian B, Dragon, Anna C, Prinz, Immo, Blasczyk, Rainer, Maecker-Kolhoff, Britta, Eiz-Vesper, Britta
• Format: Article
• Language: English
• Subjects: Activation; Adenoviruses; Antigens; CCR7 protein; CD27 antigen; CD28 antigen; CD45RA antigen; CD8 antigen; Cytokines; Cytomegalovirus; cytomegalovirus (CMV); Cytotoxicity; Depletion; donor lymphocyte infusions (DLIs); Genotype & phenotype; Good Manufacturing Practice; graft versus host disease (GvHD); Graft-versus-host reaction; Hepatitis C; Immunocompromised hosts; Immunological memory; Immunosuppression; Immunotherapy; Infections; L-selectin; Latent infection; Lymphocytes; Lymphocytes T; Memory cells; Microspheres; Mortality; naive T-cell depletion; Opportunist infection; Pathogens; Phenotypes; Transplants & implants; Viral infections; Viruses
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20061415

Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (T ) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA /CD62L naive T-cell-depleted as well as CD45RA⁺/CD62L⁺ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (T ), and CD62L depletion in loss of central memory T cells (T ). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3⁻5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present.