Presentation: Conditional Expression of IL-10 in Th1, Tr1 and Th2 lymphocytes (2007)

150 Conditional Expression of IL-10 in Th1, Tr1 and Th2 lymphocytes

Impaired regulation of inflammatory immune reactions is key to the persistence of chronic rheumatic inflammation. It has been shown that expression of interleukin-10 (IL-10) by Th lymphocytes is one of the major physiological regulatory mechanisms of immune reactions. Here we analyse the molecular requirements for IL-10 expression in effector and memory Th lymphocytes. Induction of IL-10 expression in naïve Th lymphocytes depends on initial costimulation with either IL-4, and the transcription factors Stat6 and GATA-3, or IL-12, and its downstream transcription factor Stat4. We then isolated Th effector and memory cells ex vivo according to secretion of IL-10, by the cytometric cytokine secretion assay, and after polyclonal ex vivo restimulation. Upon culture in vitro, these cells do not memorize expression of IL-10 upon further restimulations, in contrast to cells isolated according to expression of IL-4 or IFN-gamma. Their activation and proliferation is not impaired. In these cells, the il10 gene is not detectably imprinted epigenetically, and IL-10 reexpression remains conditional on continued costimulaton with inducing signals such as IL-4, for Th2 cells, or Il-2 and IL-4, for Treg, or IL-12, for Th1/Tr1 cells. So far, we have only been able to identify one condition, under which the il10 gene is imprinted for reexpression in the absence of the original instructive signal: Repeated stimulation with antigen and the instructive signal IL-4 leads to the establishment of a stable memory for IL-10, accompanied by GATA-3 induced epigenetic remodelling of the il10 gene in the cells. Such cells can rarely be isolated ex vivo. The maintained dependency of IL-10 expression of effector and memory Th lymphocytes suggests an unexpected anti-inflammatory potential of IL-12: In memory Th1 cells IL-10 expression remains dependent on IL-12, while reexpression of IFN-gamma is independent of the original inducer IL-12. The exclusion of IL-10 from the functional memory of Th1 cells probably reflects the necessity for conditional regulation of inflammatory immune responses. Therapeutic targeting of regulatory IL-10 expression in chronic rheumatic inflammation will have to consider these conditional requirements.

 H. Chang, None; J. Dong, None; I. Albrecht, None; J. Koeck, None; S. Brandenburg, None; A. Scheffold, None; A. Thiel, None; A. Radbruch, None.