Persistent CD8 T cell restricted aberrant IL-7 signaling in an atypical (T-B+NK+) SCID patient with compound heterozygous JAK3 mutations

Abstract

We report on a patient with compound heterozygous JAK3 variants manifesting as atypical (T-B+NK+) SCID. In addition, the patient displayed a severely attenuated, CD8 T cell-restricted IL-7 signaling defect that persisted for over a year after a stem cell transplant. Phosflow-cytometry and DNA sequencing A female infant was referred to our institution on day nine of life following a newborn screen TREC count=0. Immunological assessments revealed a T-B+NK+ SCID phenotype, and molecular analyses, including whole exome sequencing, identified compound heterozygous JAK3 variants (R117C and E658). 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 is >60% reduced compared to CD4 T cells). The post-transplant clinical course was complicated by identification of autoimmune responses and likely GVHD-induced ichthyosis. Collectively, these data suggest that there might be differences in factors that regulate IL-7 signaling in CD4 and CD8 T cells. These data also argue in favor of adopting whole genome sequencing approaches to adequately characterize the breadth of molecular aberrations that might potentially exist in rare cases such as this.