Il2 Receptors--molecular Regulation

Heart, Lung, And Blood Institute

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Abstract

The human interleukin-2 receptor is being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced; the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. gc is a shared chain also used by the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21, and is the protein that is mutated in XSCID. The group has focused primarily on the types of signals induced by IL-2, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate the IL-2Ra gene and other IL-2 induced genes. In the accompanying annual report, it is summarized that we have reported the characterization of a large number of genes that are regulated by gc dependent cytokines. Many of these appear to be dependent on two closely-related Stat5 proteins, denoted Stat5a and Stat5b, and we have previously demonstrated that these two proteins critically control IL-2 receptor alpha chain gene regulation by binding to two widely separated IL-2 response elements. Stat5a and Stat5b are two closely related proteins with >90% amino acid identity that are activated by IL-2. The genes encoding Stat5a and Stat5b are adjacent and the genes are located in a head-to-head orientation. An important issue is whether these closely related proteins are redundant or distinctive in their actions. To attempt to clarify this issue, Stat5a and Stat5b transgenic mice were generated to reconstitute the knockout mice. In addition, aspects of similarities vs. differences in regulation of these genes is being studied. The phenotype of Stat5a and Stat5b transgenic mice was striking. Our studies revealed that these proteins play a major role in the regulation of CD8+ T cell homeostasis and these findings were reported. Moreover, as the mice aged, they developed thymic lymphoblastic lymphoma, even though they did not exhibit a constitutively activated Jak-STAT pathway. Previously, we and others demonstrated that a constitutively activated Jak-STAT pathway correlates with and perhaps is causal in the development of certain malignancies. Thus, these thymic lymphomas may be distinctive. DNA array profiling revealed genes that are induced in the tumors but not in the non-tumor bearing transgenic mice. These findings are important in teaching more about the effects of Stat5 expression and link our earlier signaling studies to oncogenesis.