Abstract:
:It is well established that the cytokine IL-12 and the transcription factor STAT4, an essential part of the IL-12 signaling pathway, are critical components of the Th1 differentiation process in T cells. In response to pathogenic stimuli, this process causes T cells to proliferate rapidly and secrete high amounts of the cytokine IFN-γ, leading to the Th1 proinflammatory phenotype. However, there are still unknown components of this differentiation pathway. We here demonstrated that the expression of the histone methyltransferase Mll1 is driven by IL-12 signaling through STAT4 in humans and mice and is critical for the proper differentiation of a naïve T cell to a Th1 cell. Once MLL1 is up-regulated by IL-12, it regulates the proliferation of Th1 cells. As evidence of this, we show that Th1 cells from Mll1(+/-) mice are unable to proliferate rapidly in a Th1 environment in vitro and in vivo. Additionally, upon restimulation with cognate antigen Mll1(+/-), T cells do not convert to a Th1 phenotype, as characterized by IFN-γ output. Furthermore, we observed a reduction in IFN-γ production and proliferation in human peripheral blood stimulated with tetanus toxoid by use of a specific inhibitor of the MLL1/menin complex. Together, our results demonstrate that the MLL1 gene plays a previously unrecognized but essential role in Th1 cell biology and furthermore, describes a novel pathway through which Mll1 expression is regulated.
journal_name
J Leukoc Bioljournal_title
Journal of leukocyte biologyauthors
Schaller M,Ito T,Allen RM,Kroetz D,Kittan N,Ptaschinski C,Cavassani K,Carson WF 4th,Godessart N,Grembecka J,Cierpicki T,Dou Y,Kunkel SLdoi
10.1189/jlb.1A0814-375RRsubject
Has Abstractpub_date
2015-10-01 00:00:00pages
601-13issue
4eissn
0741-5400issn
1938-3673pii
jlb.1A0814-375RRjournal_volume
98pub_type
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