Turning immunological memory into amnesia by depletion of dividing T cells.
Immunological memory, defined as more efficient immune responses on antigen reexposure, can last for decades. The current paradigm is that memory is maintained by antigen-experienced "memory T cells" that can be long-lived quiescent or dividing. The contribution of T cell division to memory maintenance is poorly known and has important clinical implications. In this study, we directly addressed the role of dividing T cells in immunological memory maintenance by evaluating the consequences of their elimination. The specific ablation of dividing T cells was obtained by administration of ganciclovir to immune mice expressing the herpes simplex type 1 thymidine kinase suicide gene in T cells. We show that depletion of dividing T cells for 5 or 2 weeks suffices to abolish in vitro and in vivo memory responses against the male H-Y transplantation alloantigen or against lymphocytic choriomeningitis virus antigens, respectively. Similar results were obtained after the nonspecific elimination of all dividing cells by using hydroxyurea, a cytostatic toxic agent commonly used for cancer chemotherapy. This immune amnesia occurred in otherwise immunocompetent mice and despite the persistence of functional quiescent T cells displaying a "memory" phenotype. Thus, division of antigen-experienced T cells is an absolute requirement for immunological memory maintenance and the current concept of memory T cells is challenged.
Bellier
Bertrand
B
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7087, Université Pierre et Marie Curie, 75013 Paris, France.
Thomas-Vaslin
Véronique
V
Saron
Marie-Françoise
MF
Klatzmann
David
D
D000818:Animals; D002455:Cell Division; D005260:Female; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006918:Hydroxyurea / Q000494:pharmacology; D007156:Immunologic Memory; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism; D010641:Phenotype; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014180:Transplantation
D018960:Hyaluronan Receptors; D015774:Ganciclovir; D006918:Hydroxyurea