*Please read the Mammalian Development Background page prior to reading this page for complete background information.*
T-cells are essential component of the immune system for mammals. Without them, mammals face infection with little to no defense or means of protection. A slight cold, minor rash, or shallow cut could all become much bigger concerns without one of our greatest forms of immunity: T-cells. These very important cells have two forms: CD8+ or CD4+.
T-cells become either MHC class I-specific CD8+ T-cells or MHC class II-specific CD4+ T-cells via their progenitor (ancestor) double positive thymocytes. DP (double positive) indicates the T-cell is capable of having CD4 and CD8, but they are only viable when they are single positive, meaning only positive for CD4 or only positive for CD8.
The figure illustrates the different stages of T cell development, with the final result being single positive CD4+ or single positive CD8+.
This begs the question, what role do RUNX proteins play in the lineage choice of T-cells? Sato et al. set out to determine the answer.
Runx is the runt-related transcription factor family of genes. Transcription factors are proteins that turn genes on or off. The RUNX proteins bind to DNA and consist of regulators for haematopoiesis (development of blood cell components), osteogenesis (bone tissue formation), and neurogenesis (development of neurons).
RUNX1 and RUNX3 have demonstrated a repression of IL-4 (interleukin-4) by binding to an IL-4 silencer in both CD4+ T-cells and TH1 cells (Amelie et al. 2009). What does this mean? CD4+ is being inactivated by RUNX. Without the IL-4 silencer, RUNX3 is unable to repress IL-4 production. RUNX proteins bind to the CD8 enhancer as well. Elevated levels of CD8 occur when the Runx binds to E8I.
Sato et al. performed an immunoblot analysis that showed Runx3 binds to the CD4 silencer and CD8 enhancer (Sato et al. 2005). They also performed an RTOC (reaggregated thymus organ culture), an in-vitro experiment, to understand the mechanism regulating CD8 expression in development. The RTOC demonstrated that they become CD8 single positive cells through the CD48lo stage (Sato et al. 2005).
The figure illustrates the Runx protein expression in subpopulations. Runx3 protein is selectively expressed in CD8SP thymocytes.
Today we learned:
Lineage choice (becoming CD4+ or CD8+ T-cells) is affected by RUNX (Amelie et al. 2009)(Sato et al. 2005). CD4 is silenced by Runx and CD8 is enhanced by Runx (Amelie et al. 2009)(Sato et al. 2005).
A great review of what the paper found is also explained here.
The authors did a great job of explaining the role the RUNX protein played in silencing CD4 and developing a CD8 single positive T-cell. It also gives a comprehensive view of the other genes, proteins, and transcription factors that act as minor, yet supplemental, factors in the lineage choice process.
However, RUNX is not identified as having other functions in T-cell development outside of commitment to the CD4 lineage choice. The paper should have given more information or done other experiments to determine how RUNX functions in other parts of cell development.
Amelie Collins, Dan R. Littman, Ichiro Taniuchi. RUNX proteins in transcription factor networks that regulate T-cell lineage choice. 2009. Nature Reviews Immunology 9: 106-115.
Takehito Sato et al. Dual Functions of Runx proteins for Reactivating CD8 and Silencing CD4 at the Commitment Process into CD8 Thymocytes. 2005. Immunity 22: 317-328.