Development of Antigen Specific T Cells After HLA-Mismatched Umbilical Cord Blood Transplantation

Hematopoietic cell transplantation (HCT) is a promising strategy for the treatment of both hematologic malignancies and non-malignant hematologic dyscrasias. However, HCT is sometimes complicated by infectious diseases, especially those caused by virus. Although the most important defense mechanism to control viral replication is inducing virus-specific cytotoxic T-lymphocytes (CTLs), the details of CTL development are not fully elucidated in human transplantation. In 1978, Zinkernagel, et al., clarified in murine hematopoietic stem cell transplantation models that MHC-restricted T cells are not governed by donor HLA expressed in bone marrow stem and progenitor cells. Instead, MHC restriction is acquired by interaction with recipient thymic epithelial cells. For this reason, virus-specific T cells are not induced by the mismatched HLA. Due to the increasing number of cord blood and haplo-identical transplantations, many transplantations are being performed under HLA-mismatched conditions. However, the full repercussions of this HLA-mismatch on viral immunity are still unknown.

For 4 years we followed a 35-year-old patient (HLA-A*24:02, A*33:03) with acute myeloid leukaemia of subtype t(8;21)(q22;q22);RUNX1(AML1)-RUNX1T1(ETO) of the 2008 WHO classification who underwent cord blood (HLA-A*02:01, A*24:02) transplantation following myeloablative conditioning regimen in first complete molecular remission. We analyzed the cytomegalovirus-specific CD8(+) T cells (CMV-CTLs) through HLA-A*02:01 tetramer (HLA-mismatched) and HLA-A*24:02 tetramer (HLA-matched) by flow cytometer. T cell receptor repertoire of these tetramer-positive CMV-CTLs were analyzed by CTL cloning and CDR3 sequencing.

The patient had a short period of CMV antigenemia but not CMV disease which was well-controlled by drip infusion of the anti-viral reagent ganciclovir after transplantation. On day 41 after transplantation, only A24-restricted (HLA-matched) tetramer-positive CMV-CTLs were present. By day 195, however, A2-restricted (HLA-mismatched) tetramer-positive CMV-CTLs also appeared. We considered that the donor-derived dendritic cells (DCs) induced A2-restricted (HLA-mismatched) tetramer-positive CMV-CTLs from naïve T cells, which are originally contained in cord blood inoculum. These mismatched donor HLA restricted memory T cells existed for a long time with a wide-ranging repertoire after transplantation, however, they were considered to have a limited functional role in infection immunity because lungs and intestinal tracts epithelial cells do not express HLA-A2. Usually, cord blood with 0, 1, or 2 loci mismatches is applicable for transplantation. Since HLA-A and B loci are checked only on a serological level, there are some possibilities in which every HLA-A and B loci are mismatched in the genetic level. In such a case, induction of virus-specific CTLs from donor naïve T cells might be impaired and result in uncontrollable viral infections. The findings of this case will be helpful to understand the impact of HLA-mismatch on viral immunity.

No relevant conflicts of interest to declare.