Thymus-dependent “T” lymphocytes develop into several
effector and regulatory lineages, including the well-characterized regulatory
“helper” T (Th) cells that express the cellular differentiation marker 4 (CD4+)
and CD8+ cytotoxic T lymphocytes (CTL, or Tc) that kill virus-infected cells.
The CD4+ Th lineages further differentiate into Th1, Th2, and Treg cells that
help protect against intracellular microbes, or helminthes, or specifically
regulate immune responses, as well as Th17 cells, so-called because they make the interleukin-17 (IL17) that
is required for protecting the mucosa against infection by bacteria and
fungi.
Sunday, April 21, 2013
Recipe for Developing Th17 cells
Development of cell lineages is controlled externally by cytokines
and internally by “master” transcription factors. RORgt (retinoic-acid-receptor-related
orphan receptors gamma t) is expressed by Th17 cells and forced expression
of RORgt gene in naïve CD4+ T cells (Th0) makes them express some genes
characteristic of Th17 cells such as the IL-23 receptor and the chemokine
receptor CCR5 but not the full range of Th17 products, which requires other TFs
including STAT3, IRF4, BATF, and IkappaBzeta.
Other TFs may replace these for inducing some Th17 genes. The myriad of TFs required for more or less
full Th17 function led these investigators to try to sort out how they work
together.
The authors first looked where these implicated TFs bind on
the genome of Th0 cells treated with Th17-inducing cytokines using chromosome
immune-precipitation (ChIP). They then
compared genes that are transcribed, measured using RNA seq, in the absence of
specific TFs, reduced using siRNA, to “build a network model for Th17 cells”.
They propose that TFs BATF and IRF4 bind cooperatively and
open chromosomes to STAT3, which drives transcription of many genes including
the lineage-specifying TF RORgt. They
also identify several putative new Th17 regulators, including the AP-1 family
member Fosl2, which they belive is a key TF for Th17 development. They derive many complicated, colorful figures.
A largely understandable, intriguing single figure is 5D, copied
here, which shows that a block of Th17-related genes is increased (red) or decreased
(blue) “log2 fold” (NB the genes, named on the right, are NOT the same) in Th17
cells but not other T cell subsets (Th1, Th2) treated with siRNA suppressing
Satb1 (a “chromatin organizer"), Bcl11b (a zinc finger TF), Jmjd3 (a histone demethylase),
and the old familiar RorC (encoding RORg). But why no siRNA for Fosl2?
A validated regulatory network for th17 cell
specification. Ciofani M, Madar A, Galan
C, Sellars M, Mace K, Pauli F, Agarwal A, Huang W, Parkurst CN, Muratet M,
Newberry KM, Meadows S, Greenfield A, Yang Y, Jain P, Kirigin FK, Birchmeier C,
Wagner EF, Murphy KM, Myers RM, Bonneau R, Littman DR. Cell. 2012 Oct 12;151(2):289-303.
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