IL-4 Production by T Cells: You Need a Little to Get a Lot

nterleukin 4 is arguably one of the best-studied and most influential cytokines of the immune system. It was originally described in 1982 as a B cell stimulatory factor present in the supernatants of the phorbol ester-stimulated T cell tumor line EL-4 by Maureen Howard and Bill Paul in the Laboratory of Immunology at the National Institute of Allergy and Infections Diseases (NIAID) (1). However, it is now known that this cytokine regulates a myriad of immune functions including Ig isotype switching, class II MHC expression by B cells, and the differentiation fate of certain T cell subsets (2). In 1986 the gene encoding mouse IL-4 was cloned from Con A-activated Th cells by two laboratories and the race was on to identify the range of cells that express this molecule and determine how it is regulated (3, 4). Surprisingly, it was discovered that few if any of the conventional, nontransformed T cell lines derived in the Laboratory of Immunology at NIAID at that time produced IL-4. This observation was among the first evidence that there might be some selectivity in the cytokines expressed by Th cells. Indeed, not long afterward, Mossman and Coffman published their seminal paper showing dichotomy in CD4 Th cell subsets based on cytokine-producing potential and showed that there is a reciprocal expression pattern of IL-4 and IFN- in Th2 and Th1 cells, respectively (5). So why were the majority of clones derived in vitro of the Th1 phenotype? As we know now, there are very strict requirements for IL-4 expression by T cells. In this month's Pillars of Immunology article, "Generation of Interleukin 4 (IL-4)-producing Cells In Vivo and In Vitro: IL-2 and IL-4 Are Required for In Vitro Generation of IL-4-producing Cells," Graham Le Gros, Shlomo Ben-Sasson, Robert Seder, Fred Finkelman and Bill Paul present the first evidence that IL-4 is absolutely required for its own robust production by T cells (6).