JAK3

JAK3, short for Janus kinase 3, is a non-receptor protein tyrosine kinase in the JAK family. It participates in signaling downstream of several cytokine receptors that share the common gamma chain (CD132), including receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Upon cytokine binding, JAK3 is activated and phosphorylates itself and the associated receptor, creating docking sites for STAT transcription factors. Activated STATs dimerize and translocate to the nucleus, where they regulate gene expression to promote lymphoid cell proliferation, survival, and differentiation.

JAK3 expression is highest in hematopoietic cells, particularly T and NK cell lineages. It plays a crucial role in signaling pathways that drive development and function of these cells. Because JAK3 is mainly involved in gamma-chain cytokine signaling, its activity is essential for proper adaptive immune responses, while other JAK family members can compensate in some pathways but not fully.

Mutations in JAK3 can cause severe combined immunodeficiency (SCID). In humans, biallelic JAK3 mutations typically result in an autosomal recessive SCID phenotype characterized by T and NK cell deficiency with impaired cellular and humoral immunity; B cell numbers may be present but functionally deficient due to lack of T cell help. Diagnosis is by genetic testing and immunophenotyping. Treatments include hematopoietic stem cell transplantation and supportive care; gene therapy approaches are under investigation.

JAK3 inhibitors have been developed to modulate immune signaling and are studied for use in transplantation tolerance and autoimmune diseases. Selective JAK3 inhibition aims to reduce immune activation with fewer adverse effects than broader JAK inhibitors, though potential risks such as infections and cytopenias remain relevant. Further research continues to refine therapeutic applications and safety.