February 8, 2008

How cells switch from killers to helpers
Researchers illuminate a pivotal network of closely linked checkpoints controlling thedestiny of key immune cells.
A cell's fate - how it progresses from an immature state into one that is specialized for aparticular purpose - is a vital but poorly understood area of biology. In a critical andexciting breakthrough in this field, a team of scientists from the RIKEN Research Center
for Allergy and Immunology, the Japan Science and Technology Agency's Precursory
Research for Embryonic Science and Technology (PRESTO), and the Kyoto PrefecturalUniversity of Medicine, have described that newly uncovered details of how special
immune cells commit to a specific lineage.
In the mammalian thymus gland, precursor white blood cells mature and finally develop
into 'T' (for thymus-derived) cells. As integral components of the vertebrate body's
elaborate adaptive immune system, T cells must constantly probe their environment,using a variety of 'CD' proteins and the T cell receptor (TCR) expressed on the cellsurface, for the presence of invading pathogens.
TCR and CD proteins work closely together to identify major histocompatibility complex(MHC) proteins, which are specialized guidepost signals displayed on all cell surfaces.
Cells communicate their status to the immune system by using MHC proteins toadvertise antigens - processed protein molecules that stimulate an immune response through which the cells exchange critical information, allowing the immune system todistinguish friend from foe.
All immature T cells express two special CD proteins, CD4 and CD8, but the two main
subsets of functionally distinct mature T cells are defined by which one of these proteinsis eventually NOT displayed. Hence, CD4+CD8- helper T cells (TH) - which warn theimmune system of pathogen invasions and also help to harmonize a coordinatedimmune response - only express CD4, whereas CD4-CD8+ killer T cells (TK) - which
actually kill cells that have been infiltrated - express only CD8. Two versions of MHC
proteins, class I - recognized by TK - and class II - recognized by TH - are importantdrivers for this critical cell fate determination but much remains unknown.

Th-POK - a DNA-binding protein that regulates gene expression - was recentlyidentified as the main regulatory switch controlling T cell differentiation. Cells thatengage class II MHC complexes activate Th-POK expression, which in turn induces
CD4 production while simultaneously suppressing CD8 production, thereby committing
the cells to the TH line. The team has now linked other key mechanistic components tothis Th-POK switch.
The group had previously identified another family of DNA-binding proteins, called Runx,
which repress CD4 expression in immature and mature T cells, as important
determinants of T cell fate. Knowing that TK numbers are dramatically reduced when
Runx proteins are absent or inactivated, the scientists sought to understand how thishappens by examining genetically engineered mice that expressed mutant Runx protein
but not MHC class II proteins. The majority of MHC class I-restricted cells in these
special mice differentiated into CD4+CD8- T cells that carry the TH CD4-signature andwere also functionally similar to TH.
Th-POK gene expression levels were elevated in these Runx mutant mice and because
Runx protein complexes bound selectively to specific DNA sequences lying upstream ofTh-POK, the Runx proteins must somehow mediate the repression of Th-POK. The
team created mutant mice that were missing distinct portions of this putative Th-POK
regulatory region and found that these mutant mice had much higher Th-POK
expression levels than normal mice did. The scientists termed this control region theTh-POK silencer, concluding that it is a key determinant for regulating Th-POK
expression levels, and that this silencer activity is in turn dependent on Runx binding
complexes.
The researchers posit that other molecular players are needed to effect the Runx
silencing activity and that there is a complex antagonistic interplay between Th-POKand Runx elements. Future studies will no doubt shed more light on the genetic
programming that refines and defines our immune systems.
Original work:
Setoguchi, R., Tachibana, M., Naoe, Y., Muroi, S., Akiyama, K., Tezuka, C., Okuda, T.,
Taniuchi, I.
Repression of the Transcription Factor Th-POK by Runx Complexes in Cytotoxic T CellDevelopment. Science, published online on Feb. 8, 2008

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