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

• Published in: Immunologic research Vol. 68; no. 1; pp. 13 - 27
• Main Authors: Khanolkar, Aaruni, Wilks, Jeffrey D., Liu, Guorong, Simpson, Bridget M., Caparelli, Edward A., Kirschmann, Dawn A., Bergerson, Jenna, Fuleihan, Ramsay L.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2020; Springer Nature B.V
• Subjects: Allergology; Biomedical and Life Sciences; Biomedicine; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cord blood; Cord Blood Stem Cell Transplantation; Defects; Female; Graft-versus-host reaction; Hematopoietic stem cells; Humans; Ichthyosis; Immunology; Infant; Infant, Newborn; Interleukin 2; Interleukin 7; Interleukin-7 - metabolism; Internal Medicine; Janus kinase; Janus kinase 3; Janus Kinase 3 - genetics; Kinases; Lymphocytes; Lymphocytes T; Medicine/Public Health; Mutation; Mutation - genetics; Natural killer cells; Original Article; Phenotype; Phenotypes; Phosphorylation; Severe combined immunodeficiency; Severe Combined Immunodeficiency - diagnosis; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - therapy; Signal Transduction; Stat5 protein; STAT5 Transcription Factor - metabolism; Stem cells; Whole Exome Sequencing; IL-7R; Atypical-SCID; JAK3; pSTAT5; IL-7; CD8 T cells
• ISSN: 0257-277X; 1559-0755
• DOI: 10.1007/s12026-020-09123-x

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 (T − B + 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 (T − B + 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 T − SCID. Immunological assessments revealed a T − B + 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.