High Mutation Frequency of the PIGA Gene in T Cells Results in Reconstitution of GPI Anchor(-)/CD52(-) T Cells That Can Give Early Immune Protection after Alemtuzumab-Based T Cell-Depleted Allogeneic Stem Cell Transplantation

Loeff, F.C.; Falkenburg, J.H.F.; Hageman, L.; Huisman, W.; Veld, S.A.J.; Egmond, H.M.E. van; Meent, M. van de; Borne, P.A. von dem; Veelken, H.; Halkes, C.J.M.; Jedema, I.

doi:doi:10.4049/jimmunol.1701018

Alemtuzumab (ALM) is used for T cell depletion in the context of allogeneic hematopoietic stem cell transplantation (alloSCT) to prevent acute graft-versus-host disease and graft rejection. Following ALM-based T cell-depleted alloSCT, relatively rapid recovery of circulating T cells has been described, including T cells that lack membrane expression of the GPI-anchored ALM target Ag CD52. We show, in a cohort of 89 human recipients of an ALM-based T cell-depleted alloSCT graft, that early lymphocyte reconstitution always coincided with the presence of large populations of T cells lacking CD52 membrane expression. In contrast, loss of CD52 expression was not overt within B cells or NK cells. We show that loss of CD52 expression from the T cell membrane resulted from loss of GPI anchor expression caused by a highly polyclonal mutational landscape in the PIGA gene. This polyclonal mutational landscape in the PIGA gene was also found in CD52(-) T cells present at a low frequency in...Show moreAlemtuzumab (ALM) is used for T cell depletion in the context of allogeneic hematopoietic stem cell transplantation (alloSCT) to prevent acute graft-versus-host disease and graft rejection. Following ALM-based T cell-depleted alloSCT, relatively rapid recovery of circulating T cells has been described, including T cells that lack membrane expression of the GPI-anchored ALM target Ag CD52. We show, in a cohort of 89 human recipients of an ALM-based T cell-depleted alloSCT graft, that early lymphocyte reconstitution always coincided with the presence of large populations of T cells lacking CD52 membrane expression. In contrast, loss of CD52 expression was not overt within B cells or NK cells. We show that loss of CD52 expression from the T cell membrane resulted from loss of GPI anchor expression caused by a highly polyclonal mutational landscape in the PIGA gene. This polyclonal mutational landscape in the PIGA gene was also found in CD52(-) T cells present at a low frequency in peripheral blood of healthy donors. Finally, we demonstrate that the GPI(-)/CD52(-)T cell populations that arise after ALM-based T cell-depleted alloSCT contain functional T cells directed against multiple viral targets that can play an important role in immune protection early after ALM-based T cell-depleted transplantation.Show less

Leiden University Scholarly Publications

View statistics

In Collections

High Mutation Frequency of the PIGA Gene in T Cells Results in Reconstitution of GPI Anchor(-)/CD52(-) T Cells That Can Give Early Immune Protection after Alemtuzumab-Based T Cell-Depleted Allogeneic Stem Cell Transplantation