Altered Homeostasis of CD4+ Memory T cells in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Chronic Graft-versus-Host Disease Enhances T cell Differentiation and Exhausts Central Memory T Cell Pool

Abstract An increased risk of late infection is a serious complication after allogeneic hematopoietic stem cell transplantation (AHSCT), especially for recipients with defective CD4 + T cell recovery. Although chronic graft-versus-host disease (cGVHD) negatively influences CD4 + T cell reconstitution, the mechanisms leading to this defect are not well understood. We found that the proportion of CD27 − CD4 + T cells was remarkably increased in ASHCT recipients with cGVHD or with repetitive infectious episodes. Isolated CD27 − CD4 + T cells from ASHCT recipients had significantly shortened telomere length, displayed enhanced vulnerability to activation-induced cell death, and showed extremely reduced clonal diversity, when compared with CD27 − CD4 + T cells from healthy donors. Also, CD27 + CD4 + T cells from AHSCT recipients easily lost their expression of CD27 in response to antigen stimulation regardless of cGVHD status. Taken together, these data indicate that homeostasis of memory CD4 + T cells from AHSCT recipients is altered, and that they easily transit into CD27 − effector memory T cells. Increased in vivo T cell stimulation observed in recipients with cGVHD further promotes the transition to effector memory cells, a change that decreases the central memory CD4 + T cell pool and consequently weakens the recipient's defense against persistently infecting pathogens.