IL-2 Family Cytokines and their Receptors-- Biology of the IL-2 system

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The IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. We also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. T helper cell differentiation is an important process in the regulation of host defense. Th1 differentiation is important for host defense to viruses and other intracelllular pathogens, Th2 differentiation is vital in allergic disorders and related to helminths, and Th17 differentiation is vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease, and we previously showed that IL-2 importantly regulates expression of the IL-4 receptor and critically controls priming of cells for Th2 differentiation. Using the pmel-1 T cell receptor transgenic model of adoptive immunotherapy, we also pursued studies related to the efficacy of adoptively transferred effector cells in terms of their ability to kill turmors and found that effector T cell populations derived from naive rather than central memory CD8+ T cells mediate superior antitumor activity. These populations had distinct gene expression signatures and developmental programs, with much higher IL-2-induces expression of Eomesodermin in the central memory than naive population cells. Having previously shown that a dual specificity phosphatase, denoted DUSP5, that is induced by IL-2 and thus an IL-2 target gene and demonstrated that transgenic overexpression of DUSP5 results in a block in thymocyte development at the CD4/CD8 double positive stage, indicating a role for ERK kinases in this process and that DUSP5 contributes to immunological tolerance, we have continued work on this and another related important phosphatase. We additionally assisted in the establishment of Netpath, a public resource of curated signal transduction pathways, with the IL-2 system being highlighted as the prototype pathway. Overall, these studies help to improve our understanding of signaling by gc family cytokines. These findings clarify basic molecular mechanisms that are relevant to normal and pathological immune cell function such as allergy, autoimmunity, and cancer.