Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal transduction pathway is essential to transmit signals from transmembrane receptors to the nucleus in order to alter gene expression programs and to respond to extracellular cues. Tyrosine kinase 2 (Tyk2) was the first member of the JAK family that was identified within a screen for molecules complementing human cell lines mutant for interferon (IFN) responses. During the last decades biochemical studies and gene-targeted mice uncovered the crucial role of Tyk2 in immunity. Tyk2-deficient mice are viable and fertile but display multiple immunological defects, most prominently high sensitivity to infections and defective tumour surveillance. In contrast, absence of Tyk2 results in increased resistance against allergic, autoimmune and inflammatory diseases. In support of these data, the only patient with Tyk2 deficiency described so far displays high serum immunoglobulin E (IgE) levels and increased sensitivity to infectious diseases. Furthermore, numerous genome-wide association studies in humans propose a link between Tyk2 genetic variants and several autoimmune diseases, inflammatory diseases and tumours. Thus, Tyk2 appears as an attractive target for therapeutic intervention. Future work will be required to further delineate structure-function relationships and to fully understand the involvement of Tyk2 in immune regulatory networks.