John J. O'Shea, M.D.

Cytokines are critical for host defense, but are also key mediators of immune-mediated disease. CD4+ helper T cells are important producers of a range of such cytokines, and it is through the production of these factors that they orchestrate immune responses to eliminate a range of microbial pathogens. At the same time, though, helper T cells can also drive autoimmune disease. The goal of the Molecular Immunology and Inflammation Branch (MIIB) is to understand how CD4+ T cells differentiate to selectively produce these key immunoregulatory cytokines and to better define the molecular basis of cytokine action. By studying how engagement of cytokine receptors transduce signals that, in turn, regulate transcription factors and epigenetic events to modulate gene expression, we hope to understand, more in depth, how T cells participate in host defense and contribute to the pathogenesis of immune-mediated diseases. The insights gained from these studies are used to facilitate the development of new therapeutic approaches.

Host defense against pathogenic microorganisms requires extensive communication between innate and adaptive arms of the immune system. Signals from innate immune cells, induced by pathogens and inflammatory stimuli, drive naive CD4+ T cells to differentiate into one of several effector fates, including T helper 1 (Th1), Th2, and Th17 cells (see Figure 1). The products of differentiated T cells subsequently tailor immune responses to effectively eliminate intracellular and extracellular pathogens. Other stimuli cause CD4+ T cells to become regulatory T (Treg) cells, which dampen immune responses. Still, other stimuli allow CD4+ T cells to reside in lymph nodes and provide help to B cells; these T cells are termed follicular helper T cells. These effector and regulatory CD4+ T cell lineages protect the body from infection when appropriately activated, but can also contribute to the pathogenesis of autoimmune diseases.

We now know that a plethora of cytokines is produced by innate immune cells, and that these cytokines are critical for the development and specification of CD4 subsets. A substantial portion of cytokines (more than 60) bind to receptors that associate with a class of protein tyrosine kinases, termed Janus kinases or Jaks (illustrated in figure 2). MIIB first cloned human Jak3, a kinase predominantly expressed in immune and hematopoietic cells, and, with our colleagues, demonstrated that Jak3 associates with the common γ chain (γc). This shared cytokine receptor is used by interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21, and we found that mutations of JAK3 underlie autosomal recessive severe combined immunodeficiency. Patients suspected of having JAK3 mutations and other primary immunodeficiencies may be evaluated at the NIH Clinical Center under Protocol 99 AR0004. Because of the critical functions of Jaks in cytokine signaling, pharmacological Jak inhibitors have been developed as a new class of immunomodulary drugs. The NIH holds patents pertaining Janus kinases and identification of immune modulators (United States Patent 7,070,972 and United States Patent 7,488,808). NIAMS also has an ongoing Cooperative Research and Development Agreement (CRADA) with Pfizer, which is part of the ongoing work dedicated to understanding the mechanisms of action of Jak inhibitors in vitro and in vivo .

Dr. O'Shea is a Senior Investigator and Chief of the Molecular Immunology and Inflammation Branch, a position he has held since 2002. He studies cytokine signaling transduction. He served as the NIAMS Scientific Director of Intramural Research for twenty years, from 2005 until 2025. He also served as the Acting Director of the NIH Center for Regenerative Medicine from 2009-2011 and is an adjunct Professor in the Department of Pathology at the University of Pennsylvania.

Dr. O'Shea received his M.D. from the University of Cincinnati College of Medicine and trained in Internal Medicine at the SUNY Upstate Medical Center in Syracuse. He came to the NIH as a fellow at the National Institute of Allergy and Infectious Diseases and worked at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. He also served as a Commissioned Officer in the U.S. Public Health Service, started his own research group at the National Cancer Institute in 1989, and then moved to NIAMS in 1994 as Chief of the Lymphocyte Cell Biology Section of the Arthritis and Rheumatism Branch.

Dr. O'Shea is the author of more than 350 publications and has been elected as a member of the National Academy of Medicine. In May 2023, he was elected to the U.S. National Academy of Sciences at the conclusion of the Academy's 160th annual meeting.

He has received numerous awards including the National Academy of Medicine, National Academy of Science, American Academy of Arts and Sciences, National Academy of Inventors American Academy of Arts and Sciences, American Associate of Physicians, Master, American College of Rheumatology, American Association of Immunologists Distinguished Fellow, NIH Director's Award (eight times), U.S. Public Health Service Physician Researcher of the Year Award, Arthritis Foundation's Howley Prize, Ross Prize in Molecular Medicine, Interferon and Cytokine Society Millstein Prize, American Association of Immunologists' Steinman Award for Human Immunology, American Society for Clinical Investigation Harrington Prize.