SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling

•ZAP70 deficiency can present with severe live vaccine adverse events.•ZAP70 deficiency is not detected by TREC-based newborn screening.•SYK partially compensates for human ZAP70 deficiency.•Polyclonal SYK− CD4 T cells have severely impaired TCR signaling.•Oligoclonal SYKinter CD8 T cells feature residual TCR signaling.

Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients. One patient carried a novel non-sense mutation (p.A495fsX75); the other a previously described misense mutation (p.A507V). In contrast to CD4 T cells, the majority of the few CD8 T cells showed expression of the ZAP70-related tyrosine kinase SYK that correlated with residual TCR signaling including calcium flux and degranulation. Our findings highlight the differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells.