Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function

Background
The capacity of CD8+T cells to control infections and mediate anti-tumor immunity requires
the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8+ T cell effector function
and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T cell immunity in humans is unknown.ObjectiveTo determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease
pathogenesis in primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade.

Methods
Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules
in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in STAT1, STAT3 or IL21R were used to assess the respective roles of these genes in human CD8+ T cell differentiation in vivo and in vitro.

Results
Mutations in STAT3 and IL21R, but not STAT1, lead to a decrease in multiple memory CD8+ T cell subsets in vivo, indicating that STAT3 signaling – possibly downstream of IL-21R - regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naïve CD8+ T cells. However, this defect was overcome by TCR engagement.

Conclusion
The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3 and IL-21R-deficient individuals.