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Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling. ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarship

Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling., SOCS2 is a key regulator of growth hormone and cytokine signaling, which recognizes phosphotyrosine (pTyr)-modified targets via a central SH2 domain. Here, the authors discover and characterize an exosite on this SH2 domain that can bind a non-phosphorylated peptide to enhance SOCS2:pTyr affinity.

Natural killer (NK) cells are innate immune cells with an intrinsic ability to detect and kill infected and cancerous cells. The success of therapies targeting immune checkpoints on CD8 cells has intensified interest in harnessing the cytolytic effector functions of NK cells for new cancer treatments. NK cell development, survival and effector activity is dependent on exposure to the cytokine interleukin (IL)-15. The suppressor of cytokine (SOCS) proteins (CIS; SOCS1-7) are important negative regulators of cytokine signaling, and both CIS and SOCS2 are reported to have roles in regulating NK cell responses. Their immunomodulatory effects on NK cells suggest that these SOCS proteins are promising targets that can potentially form the basis of novel cancer therapies. Here we discuss the role of NK cells in tumor immunity as well as review the role of the SOCS proteins in regulating IL-15 signaling and NK cell function.

Immune checkpoint inhibitors harness the power of the immune system to fight cancer. The clinical success achieved with antibodies against the inhibitory T cell receptors PD-1 and CTLA4 has focused attention on the possibility of manipulating other immune cells, in particular those involved in innate immunity. Here we review the role of innate lymphoid cells (ILCs) and their contribution to tumor immunity. As the prototypical ILC, the natural killer (NK) cell has an intrinsic ability to detect and kill cancer cells. NK cells are dependent on the cytokine interleukin (IL)-15 for their development and effector activity. We discuss the role of the Suppressor of cytokine (SOCS) proteins in negatively regulating IL-15 and NK cell responses and the potential for targeting these small intracellular regulators as new immune checkpoints.