title: Depletion-Resistant CD4 T Cells Enhance Thymopoiesis During Lymphopenia.
abstract: Lymphoablation is routinely used in transplantation, and its success is defined by the balance of pathogenic versus protective T cells within reconstituted repertoire. While homeostatic proliferation and thymopoiesis may both cause T cell recovery during lymphopenia, the relative contributions of these mechanisms remain unclear. The goal of this study was to investigate the role of the thymus during T cell reconstitution in adult allograft recipients subjected to lymphoablative induction therapy. Compared with euthymic mice, thymectomized heart allograft recipients demonstrated severely impaired CD4 and CD8 T cell recovery and prolonged heart allograft survival after lymphoablation with murine anti-thymocyte globulin (mATG). The injection with agonistic anti-CD40 mAb or thymus transplantation only partially restored T cell reconstitution in mATG-treated thymectomized mice. After mATG depletion, residual CD4 T cells migrated into the thymus and enhanced thymopoiesis. Conversely, depletion of CD4 T cells before lymphoablation inhibited thymopoiesis at the stage of CD4-CD8-CD44hiCD25+immature thymocytes. This is the first demonstration that the thymus and peripheral CD4 T cells cooperate to ensure optimal T cell reconstitution after lymphoablation. Targeting thymopoiesis through manipulating functions of depletion-resistant helper T cells may thus improve therapeutic benefits and minimize the risks of lymphoablation in clinical settings.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH.
authors.forename: K
authors.initials: K
authors.lastname: Ayasoufi
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: R
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: A
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D000818:Animals; D005260:Female; D016027:Heart Transplantation; D007156:Immunologic Memory; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000637:transplantation*
keywords: Immunosuppressant; T cell biology; basic (laboratory) research/science; immunobiology; immunosuppression/immune modulation; immunosuppressive regimens; induction; lymphocyte biology; polyclonal preparations: rabbit anti-thymocyte globulin; thymus/thymic biology