Expression of the cytokine interleukin-2 is controlled by allelic exclusion

Interleukin-2 (IL-2) is important for autocrine cell cycle progression, and plays a major role in the paracrine and endocrine regulation of immune responses. In vitro analysis for IL-2 production demonstrated that the bulk of T cells heterozygous (+/-) for a deficient IL-2 gene produced only half as much cytokine in comparison to wild-type (+/+) T cells. Subsequent studies at a single cell level revealed that only every other +/- T cell produced IL-2 but did so as efficiently as +/+ T cells. To further investigate whether IL-2 transcription is mono-allelic we performed single cell analysis on T cells of F1 (M. musculus x M. spretus) mice. Using RT-PCR for strain-specific differences, we demonstrated that only one but not both alleles are transcribed in a single cell upon activation. Fluorescent in situ hybridization (FISH) of +/+ T cells in S phase of the cell cycle revealed further an asynchronous replication of the IL-2 allele, a hallmark of allelic silencing. Taken together, these results demonstrate an allele-specific restriction in IL-2 gene transcription. Our findings detail a novel mechanism for the control of a non-imprinted, autosomal, non-receptor molecule. This transcriptional control may provide an additional fail-safe device to assure precise regulation of IL-2 production.