MRC National Institute for Medical Research, London
Science for Health
The importance of IL-12 - a classic paper by Anne O’Garra
30 September 2008
A Pillar of Immunology is a cornerstone scientific discovery that has had a significant influence on the underlying structure of the field of immunology. The pillars, all published between 15 and 40 years ago, are selected by a panel of renowned immunologists on behalf of the Journal of Immunology, a leading journal in the field of immunology. Since 2004 the Journal of Immunology has reprinted nearly 60 such papers. These articles are selected because they have changed the way scientists thought about a problem or its solution and they are distinguished by clarity of expression in reporting, both of the data and in its interpretation.
Anne O'Garra's 1993 Science paper has been selected as a Pillar and William Paul wrote an accompanying commentary on the article.
The 1993 Science paper by Hsieh, Macatonia, Tripp, Wolf, O'Garra and Murphy is a landmark in the progress made in understanding the mechanisms of differentiation of naive CD4+ T cells. The lessons learned from the study of this pathway and that of the pathway of Th2 differentiation have instructed our knowledge of all aspects of CD4+ T cell differentiation and have had an enormous influence on our understanding of how CD4+ T cells mount effective responses against distinct pathogens and how abnormalities in these cells lead to an array of immunopathologic conditions, including tissue-specific and generalized autoimmune disorders and asthma and allergic disorders.
William Paul
This was a very exciting time when Ken Murphy's and my laboratories joined forces to define systems and prove that CD4+ Th1 and Th2 cells, producing different cytokines, arose during a programmed differentiation process by signals directed at the naive T cell. We were both just starting our own labs: Ken at Washington University, St. Louis; myself at the DNAX Research Institute, California, and we agreed to collaborate on this problem. Chyi Song Hsieh spent time at DNAX and both labs engaged in intense scientific discussions which paved the way forward. The question as to whether Th1 and Th2 cells actually represented discrete Th effector subsets was under debate, many researchers suggesting that they were a clonal artifact. Using de novo reductionist systems we defined the pathway of Th1 differentiation first described in this Science paper. The key finding in this paper was that pathogens and their products direct the development of appropriate types of effector T cell immune responses, not by directly stimulating the T cells themselves, but by interacting with cells that present antigen to T cells. We showed that pathogen-derived products differentially induced these antigen presenting cells to produce IL-12, which directs the development of Th1 cells capable of effective eradication of intracellular pathogens.
The cytokine IL-12 was a dominant factor in inducing Th1 fate determination in CD4+ T cells. This led to many subsequent studies both from each of our own labs and from others on the molecular basis of both Th1 and Th2 cell differentiation and function. Also these systems have been used subsequently in numerous studies to identify the factors responsible for the differentiation of other CD4+ Th effector cells. We had a really exciting and fun time - as the song says: Those were the day...
Anne O'Garra
Original articles
The commentary is published in:
William E. Paul (2008).
Th1 Fate Determination in CD4+ T Cells: Notice Is Served of the Importance of IL-12!
Journal of Immunology, 181, 4435-4436. Full text at publisher.
The 1993 research findings are published in full in:
Chyi-Song Hsieh, Steven E. Macatonia, Catherine S. Tripp, Stanley F. Wolf, Anne OGarra, and Kenneth M. Murphy.
Pillars Article: Development of TH1 CD4+ T Cells Through IL-12 Produced by Listeria-Induced Macrophages. 1993. Science 260(5107): 547–549
Journal of Immunology, 181, 4437-4439.
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