Interleukin 2 - History

History

IL-2, a soluble hormone-like mediator of the immune system, was the first interleukin molecule to be identified and characterized.

A soluble activity that was found mitogenic for lymphocytes was first described simultaneously by Shinpei Kasakura and Louis Lowenstein, plus Julius Gordon and Lloyd MacLean, at McGill University in 1965 in the culture media of mixed leukocytes and named Blastogenic Factor (BF). The publication of this discovery in Nature was the first indication that the immune system might be regulated by soluble factors, other than immunoglobulins, and galvanized the field into looking for and further characterizing these entities. Between 1965 and the mid 1970s a myriad of soluble "activities", each given a different name, were reported in the media conditioned by leukocytes in culture. However, the molecular nature of these "activities" remained obscure until the work of Kendall Smith and his team at Dartmouth Medical School.

Smith's group created the first long-term antigen-specific cytotoxic T cell lines, and then the first monoclonal functional T cells. They then used these cloned T cell lines as target cells in developing a rapid, quantitative assay for the activity that they named T cell growth factor (TCGF). They then used this new bioassay to purify the molecule responsible for the TCGF activity, and raised monoclonal antibodies reactive with it, which were then used to purify the molecule to homogeneity in milligram amounts, a first for this new class of molecules.

Smith's group also showed TCGF to be the first cytokine to mediate its effects via a specific IL-2 receptor, and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library by Tadatsugu Taniguchi's group. Thus, despite being designated the number 2 interleukin, it was the first interleukin molecule, receptor, and gene to be discovered. It was designated the number 2 interleukin because Smith's data indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells). These data served as the scientific rationale for the creation of the interleukin nomenclature, anticipating that more molecules would be discovered. Now, in 2012, there are 37 interleukin molecules.

After the biochemical biological and genetic characteristics of IL-2 became known, Shinpei Kasakura's group performed a series of experiments defining BF almost twenty years after its first description. He was able to show that BF was distinct from IL-2, B cell growth factor and IL-1. The major distinguishing characteristic was that BF was mitogenic for unstimulated lymphocytes, whereas IL-2 mitogenic activity required prior antigenic activation to stimulate the expression of IL-2Rs. Thus, BF was probably equivalent to IL-15, which was not discovered until three years later.