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25.03.2020 | Original Article

A case of aberrant CD8 T cell–restricted IL-7 signaling with a Janus kinase 3 defect–associated atypical severe combined immunodeficiency

Zeitschrift:
Immunologic Research
Autoren:
Aaruni Khanolkar, Jeffrey D. Wilks, Guorong Liu, Bridget M. Simpson, Edward A. Caparelli, Dawn A. Kirschmann, Jenna Bergerson, Ramsay L. Fuleihan
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s12026-020-09123-x) contains supplementary material, which is available to authorized users.

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Abstract

Severe combined immunodeficiency (SCID) disorders compromise lymphocyte numbers and/or function. One subset of SCID typically affects T cell and Natural Killer (NK) cell development in tandem (TB+NK) due to mutations arising in the genes encoding the common γ chain or Janus Kinase 3 (JAK3). In rare circumstances, mutations in the JAK3 gene have been reported to cause atypical SCID that selectively affects T cells (TB+NK+). Here we describe a case involving a female infant who was referred to our institution on day nine of life following an abnormal newborn screen result for TSCID. Immunological assessments revealed a TB+NK+ phenotype and molecular analyses, including whole exome sequencing, identified compound heterozygous JAK3 variants (R117C and E658K). Pre-transplant phosflow analyses revealed a persistent IL-7 signaling defect, based on phospho-STAT5 measurements, only in CD8 but not CD4 T cells. Intriguingly, phospho-STAT5 signals in response to IL-2 stimulation were not affected in either CD4 or CD8 T cells. The pre-transplant clinical course was unremarkable, and the patient received a cord-blood stem cell transplant on day 716 of life. Post-transplant monitoring revealed that despite normalization of lymphocyte counts, the CD8 T cell-restricted IL-7 signaling defect was still evident at day 627 post-transplant (phospho-STAT5 signal in CD8 T cells was > 60% reduced compared with CD4 T cells). The post-transplant clinical course has also been complicated by identification of autoimmune responses and likely GVHD-induced ichthyosis. To the best of our knowledge, this report represents the third case of JAK3-associated atypical SCID reported in the literature.

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