An inflammatory inference

The protein tags that adorn immune cells and engage with receptors to promote inflammation in the body’s endothelial tissues are not what they were thought to be. A KAUST investigation has identified the true surface proteins expressed by T-cells that mediate this molecular liaison, a finding that could help scientists control inflammation that has gone haywire¹.

“This has significant implications for developing targeted therapies to combat inflammatory diseases, such as psoriasis and rheumatoid arthritis,” says Jasmeen Merzaban, a biochemist at KAUST who led the research. 

The receptor with which the surface proteins on T-cells interact is known as E-selectin. This cell adhesion molecule is expressed by tissues that line the inner surface of blood vessels: it acts as a kind of Velcro that clings to T-cells when the endothelium needs to fight off infections from bacteria or viruses.

The trouble is that E-selectins can also trigger inflammation when there are no such microbial invaders. These aberrant inflammatory signals can cause autoimmune diseases. However, blocking the hitching of E-selectin to T-cells could help reverse that problematic immune reaction.

For more than a decade, researchers knew of only two surface proteins expressed by T-cells that could serve as binding partners, or ligands, for E-selection. Yet, mouse studies had shown that reducing expression of these two proteins—PSGL-1 and CD43—was not sufficient to eliminate the crosstalk between E-selectin and T-cells. That suggested to Merzaban that some other E-selectin ligands might be at play.

She and her graduate students Amal Ali and Ayman Abuelela used a mass spectrometry approach to identify the full repertoire of E-selectin ligands expressed by T-cells. They detected 10 such proteins, one of which they explored in greater detail owing to its known function as an E-selectin ligand expressed by blood stem cells, the precursors of T-cells.

This protein, called CD44, is also expressed on the surface of both helper and killer T-cells, where it binds E-selectin, the researchers found. Merzaban and her team had discovered a third E-selectin ligand. But, as it turned out, not all these ligands contribute to T-cell tethering.

The researchers knocked down the expression of all three ligands, individually and in combination. They discovered that CD44—not CD43—worked with PSGL-1 as the E-selectin ligands implicated in inflammation.

They confirmed the clinical relevance of these findings by looking at T-cells isolated from patients with psoriasis, a common inflammatory skin condition—which means that “targeting these ligands could be a viable option to treat skin diseases,” explains Ali. 

References

1. Ali, A.J., Abuelela, A.F. & Merzaban, J.S. An analysis of trafficking receptors shows that CD44 and P-selectin glycoprotein ligand-1 collectively control the migration of activated human T-cells. Frontiers in Immunology 8, 492 (2017).| article