Lecture - John O´Shea
Basic and Applied Cytokine Signaling: From Jakinibs to Super-enhancers
NIAMS, Scientific Director, National Institute of Health, Bethesda, USA
Cytokines are critical for all phases of immune responses, with key functions ranging from supporting hematopoiesis to promoting differentiation of immune cells. In addition to their role in host defense and immunoregulation, cytokines are major contributors to the pathophysiology of immune-mediated disease. Understanding the molecular basis of action therefore represents a fascinating basic problem in cell signaling that yields clinically relevant insights. A large subset of cytokines exerts its effects through Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway. Our findings that JAK3 mutations underlie autosomal recessive severe combined immunodeficiency led us to propose that JAK inhibitors would represent a new class of immunomodulatory drugs, which resulted in two patents. At present, there are three FDA-approved JAK inhibitors and many others in late-phase clinical trials including ongoing trials at the NIH.
Deciphering precisely how external and intrinsic signals combine to regulate cell behavior remains a challenge. We have found that cytokines acting via STATs have a major impact on the enhancer landscape of differentiating helper T cells, an important class that includes “superenhancers.” A major goal of the lab at present is to understand how intrinsic lineage-defining transcription factors work in concert with signal-dependent transcription factors like STATs to alter the epigenomes of immune cells and how this relates to genetic associations with autoimmune disease and drug action.
Ronald van Vollenhoven, Karolinska Institutet
Tatiana Goriatcheva, Nobel Office, Nobel Forum,
tel. 524 87805