Stochastic monoallelic expression of IL-10 in T cells.
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.
Calado
Dinis Pedro
DP
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Paixão
Tiago
T
Holmberg
Dan
D
Haury
Matthias
M
D000483:Alleles; D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics*; D051379:Mice; D023421:Models, Animal; D011336:Probability; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013269:Stochastic Processes; D014158:Transcription, Genetic
D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10