A previously unrecognized biochemical mechanism by which the immune system reins in the tissue-destroying activities of T lymphocytes has been identified by researchers at the Weizmann Institute in Israel. Their studies centered on two key activities associated with T-cell invasion of infected tissues. One of them, the release of the enzyme heparanase that punches holes in the endothelial connective tissue of blood vessels, enables the T cell to exit the blood system and squeeze into an inflamed area
The other, the release by T cells of the signal protein TNF-alpha, sends out a rallying call to bring additional inflammatory cells into battle.
In a paper published in the Proceedings of the National Academy of Sciences (Vol 92, No 11), Prof. Irun Cohen and Dr. Ofer Lider of the Institute's Department of Cell Biology showed that these two activities are interrelated. They found that small, specifically modified sugar units released by the breakdown of sugar-containing polymers in connective tissues are picked up by invading T cells and other varieties of white blood cells. These sugar molecules, they observed, quench the ability of the cells to produce TNF-alpha.
Therefore when many blood cells are busy entering a particular infected region, releasing many sugar molecules, the cells produce reduced amounts TNF-alpha. This represents a newly discovered control mechanism that limits T-cell entry when sufficient numbers of these cells are already at work.
According to Cohen and Lider, this finding has great relevance to autoimmmune diseases such as arthritis, multiple sclerosis, and thyroiditis.
In a previous study carried out with Drs. Dalia Gilat, Rami Hershkovitz, and Liora Cahalon of the Weizmann Institute and Dr. Israel Vlodvavsky of the Hadassah-Hebrew University Medical Center, Lider identified yet another possible regulatory mechanism of T-cell action -- one that increases T-cell recruitment. This collaboration showed that the connective tissue-breakdown enzyme heparanase can only operate as an enzyme when acidity levels are high, conditions characteristic of inflammation and tumor growth, a finding published in the Journal of Experimental Medicine.
The researchers believe that normal levels of acidity, which serve to bind heparanase to the sugar-containing polymers in the extracellular supporting matrix of organs without degrading these polymers, may serve to enable the T cells to migrate and interact with connective tissue once they have left the blood stream and entered an inflamed tissue.
Heparanase is known to pave the way not only for T cells, but also for mlignant metastases. "Therefore," says Lider, "we may some day be able to inhibit metastases by adjusting the pH in the vicinity of a tumor, thereby preventing heparanase from clearing a path for cancerous cells."