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Georg A. Hollander,* Saulius Zuklys,^ Corinne Morel,^ Emiko Mizoguchi, Kathrine Mobisson, Stephen Simpson,^^ Cox Terhorst, William Wishart, David E. Golan, Atul K. Bhan, Steven J. Burakoff*
The lymphokine interleukin-2 (IL-2) is responsible for autocrine cell cycle progression and regulation of immune responses. Uncontrolled secretion of IL-2 results in adverse reactions ranging from anergy, to aberrant T cell activation, to autoimmunity. With the use of fluorescent in situ hybridization and single-cell polymerase chain reaction in cells with different IL-2 alleles, IL-2 expression in mature thymocytes and T cells was found to be tightly controlled by monoallelic expression. Because IL-2 is encoded at a nonimprinted autosomal locus, this result represents an unusual regulatory mode for controlling the precise expression of a single gene.
IL-2 is a growth factor important in the regulation and differentiation of lymphocytes and natural killer cells (1). Produced by a subpopulation of activated T cells, IL-2 also plays a pivotal role in the generation of an adoptive immune response. Decreased secretion or the complete absence of IL-2 in humans is associated with primary and secondary immunodeficiencies (2). Mice homozygous for an IL-2 null mutation (IL-2^sup -/-^) have a compromised immune system with alterations of both cellular and humoral functions (3). Overproduction of IL-2 results in an impaired immune response with autoimmunity, breaking of clonal anergy, and suppression of certain T cell functions (4). IL-2 expression, therefore, is firmly controlled by multiple signaling pathways emanating from the T cell receptor and antigen-independent coreceptors (5). These signals regulate the transcriptional control of ubiquitous and T cellspecific factors, which transactivate transcription of the gene encoding IL-2 in vivo through binding to the promoter and enhancer sequences using an all-or-nothing mechanism (5). Coreceptors also transduce signals that stabilize IL-2 mRNA (6).
The number of functional IL-2 alleles may also determine the amount of IL-2 produced. Therefore, we investigated whether T cells heterozygous for the IL-2 null mutation produce less IL-2 than wild-type T cells. We stimulated CD4^sup +^ T cells purified from wildtype and heterozygous mice. The amount of IL-2 produced by concanavalin A (Con A)treated IL-2+/- T cells was decreased by half when compared with that produced by T cells from wild-type mice (Fig. 1 ). As expected, Con A stimulation of IL-2-/- T...