Immunosenescent Characteristics of T Cells in Young Patients Following Haploidentical Stem Cell Transplantation from Parental Donors

Introduction: Pediatric and adolescent patients in need of allogeneic hematopoietic stem cell transplantation generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in pediatric recipients. Therefore, in this study paired samples were collected at the same time from donors and recipients of haploidentical hematopoietic stem cell transplantation (HaploSCT).

Methods: We conducted flow cytometry-based phenotypic and functional analyses and telomere length measurements of 21 paired T-cell sets from parental donors and children who received T cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy) at Seoul National University Children's Hospital between February 2014 and January 2017. The conditioning regimen was comprised of targeted busulfan (total target area under the curve, 75,000 mg•h/L) with intensive pharmacokinetic monitoring, fludarabine and cyclophosphamide.

Results: Fourteen pediatric, adolescent, and young adult patients with malignant disease and seven with nonmalignant disease were included with a median post-transplantation period of 16.9 months (range, 12.4-38.8). Senescent T cells, CD28- or CD57+ subsets of both CD4+ and CD8+ T cells, were significantly expanded in patients compared with parental donors. Further, not only CD4+CD28- T cells, but also CD4+CD28+ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR mediated proliferation capacity was comparable. Of note, the telomere length in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. We also found that the patients had a higher level of γ-H2AX-expressing CD28- senescent T cells compared with the donors, which is used as a DNA damage marker. Regression analysis showed that senescent features of CD4+ and CD8+ T cells in patients were influenced by donor age and the frequency of CD28- cells, respectively.

Conclusions: Our data suggest that T cells undergo premature immunosenescent changes and exhibit functional defects in pediatric HaploSCT recipients. Further, there is an increased level of DNA damage in patient CD4+ T cells compared to those of parental donors. Therefore, long-term, comprehensive immune monitoring of these patients is necessary.