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

National Heart, Lung, And Blood Institute

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Abstract

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 extremely 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. In the past year, we reported 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 important phosphatase. The closest cytokine system to IL-2 is that of IL-15 in that both cytokines share IL-2Rb and the gc but have distinctive alpha chains. IL-15 is particularly important for NK-cell development and function and CD8+ T cell homeostasis. As compared to IL-2Ra, IL-15Ra has a larger cytoplasmic domain. We studied the importance of the IL-15 receptor cytoplasmic domain. IL-15 signals at least in part through a process known as transpresentation whereas so far this mechanism of signaling has not been shown for IL-2. To investigate the role of the IL-15Ra cytoplasmic domain, we generated a chimeric receptor molecule with the extracellular and transmembrane portions of IL-2Ra but the cytoplasmic domain of IL-15Ra and knock-in mice were generated. We performed a range of studies in cells lines and in these mice. Adoptive transfer experiments with the chimeric receptor revealed that the IL-15Ra introcytoplasmic domain is required for normal IL-15Ra function but not for transpresentation. 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.