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Stochastic Monoallelic Expression of IL-10 in T Cells¹

Dinis Pedro Calado^2,*, Tiago Paixão^*, Dan Holmberg and Matthias Haury^3,*

^* Instituto Gulbenkian de Ciência, Oeiras, Portugal; and Institute for Medical Biology, University of Umeå, Umeå, Sweden

IL-10 is a potent anti-inflammatory and immunomodulatory cytokine, exerting major effects in the degree and quality of the immune response. Using a newly generated IL-10 reporter mouse model, which easily allows the study of IL-10 expression from each allele in a single cell, we report here for the first time that IL-10 is predominantly monoallelic expressed in CD4⁺ T cells. Furthermore, we have compelling evidence that this expression pattern is not due to parental imprinting, allelic exclusion, or strong allelic bias. Instead, our results support a stochastic regulation mechanism, in which the probability to initiate allelic transcription depends on the strength of TCR signaling and subsequent capacity to overcome restrictions imposed by chromatin hypoacetylation. In vivo Ag-experienced T cells show a higher basal probability to transcribe IL-10 when compared with naive cells, yet still show mostly monoallelic IL-10 expression. Finally, statistical analysis on allelic expression data shows transcriptional independence between both alleles. We conclude that CD4⁺ T cells have a low probability for IL-10 allelic activation resulting in a predominantly monoallelic expression pattern, and that IL-10 expression appears to be stochastically regulated by controlling the frequency of expressing cells, rather than absolute protein levels per cell.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Fundação para a Ciência e Tecnologia (FCT) and Fundo Europeu de Desenvolvimento Regional by the Grants POCTI/P/BIO/10091/98 and POCTI/SAU/MMO/61652/04. D.P.C. and T.P. are supported by Ph.D. fellowships from FCT.

² Current address: The CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston MA 02115.

³ Address correspondence and reprint requests to the current address: Dr. Matthias Haury, EICAT, European Molecular Biology Laboratory, Meyerhofstr. 1, D-69117 Heidelberg, Germany. E-mail address: haury{at}embl.de

⁴ Abbreviations used in this paper: SHA, short homology arm; LHA, long homology arm; NaBU, sodium butyrate; neo^R, neomycin resistance; rm, recombinant murine; TSA, trichostatin A; UTR, untranslated region.

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