title: Familial NK cell deficiency associated with impaired IL-2- and IL-15-dependent survival of lymphocytes.
abstract: We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syndrome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 alphabeta T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype of impaired survival of both fresh and herpesvirus saimiri-transformed T cells, in the surviving child. Clearly, NK cells could not be studied. However, peripheral blood T lymphocytes displayed excessive apoptosis ex vivo. Moreover, the survival rates of CD4 and CD8 alphabeta T cell blasts generated in vitro, and herpesvirus saimiri-transformed T cells cultured in vitro, were low, but not nil, following treatment with IL-2 and IL-15. In contrast, Fas-mediated activation-induced cell death was not enhanced, indicating a selective excess of cytokine deprivation-mediated apoptosis. In keeping with the known roles of IL-2 and IL-15 in the development of NK and CD8 T cells in the mouse model, these data suggest that an impaired, but not abolished, survival response to IL-2 and IL-15 accounts for the persistent lack of NK cells and the transient CD8 alphabeta T lymphopenia documented in vivo. Impaired cytokine-mediated lymphocyte survival is likely to be the pathogenic mechanism underlying this novel form of inherited and selective NK deficiency in humans.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM Unité 550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France, European Union (EU).
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mention
authors.forename: Benoit
authors.initials: B
authors.lastname: Pasquier
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Fleckenstein
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Laure
authors.initials: L
authors.lastname: Gineau
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Carel
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D007223:Infant; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000473:pathology*; D008214:Lymphocytes / Q000473:pathology*; D008231:Lymphopenia / Q000209:etiology
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2