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P38mapk Signals

Akamatsu, M;Mikami, N;Ohkura, N;Kawakami, R;

Naturally occurring CD4+ regulatory T (Treg) cells expressing the transcription factor forkhead box protein 3 (Foxp3) are essential for the maintenance of immunological self-tolerance and homeostasis (1). Anomalies of Foxp3+ natural Treg (nTreg) cells in number or function, such as those associated with loss-of-function mutations of the Foxp3 gene, cause various immunological diseases including autoimmune disease, allergy, and inflammatory bowel disease (1, 2). Moreover, increasing the number of Foxp3+ nTreg cells or augmenting their suppressive function is able to treat immunological diseases and control graft rejection in organ transplantation (1). Although the majority of nTreg cells are produced by the thymus as a functionally distinct and mature T cell population (tTreg cells), conventional T (Tconv) cells in the periphery can acquire similar Treg phenotype and function [peripherally induced Treg (pTreg) cells], for example, in response to a particular species of commensal bacteria in the intestine (3). On the basis of these findings on physiological generation of Foxp3+ Treg cells in the thymus and the periphery, a promising ap- proach for promoting antigen-specific immune suppression is the development of methods for converting antigen-specific Tconv cells,
especially effector or memory T cells mediating harmful immune responses, into functionally stable Foxp3-expressing Treg cells in vivo and in vitro.
It has been well established that in vitro antigenic stimulation in the presence of transforming growth factor– (TGF-) is able to elicit Foxp3 expression in Tconv cells (4, 5). This in vitro TGF-–dependent generation of induced Treg (iTreg) cells is, however, only attainable from naïve Tconv cells, not from effector or memory T cells, and hindered by the presence of proinflammatory cytokines (4, 5). In addition, TGF-–induced iTreg cells are unstable in sustaining in vivo suppressive function mainly because of their failure to acquire stable Treg-specific epigenomic changes in Foxp3 and other Treg signature genes, which limits their therapeutic application (5–7). These findings prompted us to search for chemical compounds that can convert not only naïve but also effector or memory Tconv cells into functionally stable, antigen-specific Foxp3+ Treg cells in a TGF-–independent manner even in the presence of proinflammatory cytokines.
We conducted a screen of chemical compounds for the in vitro capacity to generate Foxp3+ T cells from Tconv cells. We found that pharmacological inhibition of cyclin-dependent kinase 8 (CDK8) and its paralog CDK19, which are reversibly associated with the Mediator complex and mainly control the function of transcription factors

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