Jak3 deficiency blocks innate lymphoid cell development.

Abstract

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3, generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.

• Authors: M L Robinette, M Cella, J B Telliez, T K Ulland, A D Barrow, K Capuder, S Gilfillan, L-L Lin, L D Notarangelo, M Colonna
• Journal: Mucosal immunology (Mucosal Immunol) Vol. 11 Issue 1 Pg. 50-60 (01 2018) ISSN: 1935-3456 [Electronic] United States
• PMID: 28513593 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• PF-06651600
• Piperidines
• Pyrimidines
• Pyrroles
• Interferon-gamma
• tofacitinib
• Janus Kinase 3

Topics

• Animals
• Arthritis, Rheumatoid (drug therapy)
• Bone Marrow Cells (physiology)
• Cell Differentiation (genetics)
• Cell Proliferation (genetics)
• Cells, Cultured
• Humans
• Immunity, Innate
• Interferon-gamma (metabolism)
• Janus Kinase 3 (antagonists & inhibitors, genetics)
• Killer Cells, Natural (physiology)
• Mice
• Mice, Mutant Strains
• Mutation (genetics)
• Phenotype
• Piperidines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)
• Severe Combined Immunodeficiency (genetics)