Familial NK cell deficiency associated with impaired IL-2-and IL-15-dependent survival of lymphocytes

C Eidenschenk, E Jouanguy, A Alcaļs… - The Journal of …, 2006 - journals.aai.org
C Eidenschenk, E Jouanguy, A Alcaļs, JJ Mention, B Pasquier, IM Fleckenstein, A Puel…
The Journal of Immunology, 2006journals.aai.org
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 αβ 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 …
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 αβ 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 αβ 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 αβ 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.
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