T-lymphocyte differentiation and proliferation in the absence of the cytoplasmic tail of the common cytokine receptor γ(c) chain in a severe combined immune deficiency X1 patient

Abstract

Mutation of the γ(c) chain common to interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors has been shown to be responsible for the X chromosome-linked severe combined immune deficiency (SCIDX1). Human SCIDX1 patients are characterized an absence of T and natural killer cell differentiation. We report the case of a SCIDX1 patient who first had few detectable peripheral T cells, then developed, after haploidentical T- depleted bone marrow transplantation (BMT), up to 2,000/μL autologous T cells. These T cells have persisted over 8 years after BMT and were able to proliferate in the presence of mitogens and of some antigens, although to a lesser extent than control T cells. A stop mutation was identified which predicts that the major part of the cytoplasmic tail of γ(c) is truncated. This mutation does not affect high-affinity IL-2 binding, but it partly decreases IL-2 endocytosis and prevents the downmodulation of the IL-2- receptor β chain and the tyrosine phosphorylation of Jak 3 protein in response to IL-2. This report raises questions concerning the role of the γ(c) chain in IL-2 receptor endocytosis and in T-cell development and differentiation.