Which genes drive ‘exhausted’ T cells? New study provides clues

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T-cell therapy is being used, over multiple trials, for the treatment of a variety of severe diseases. Great progress has been made in recent years with advances in areas such as CAR-T therapy, where the power of genetic engineering has magnified the capabilities of cell-based therapy.

With this in mind, it has been known that the pattern of genes in exhausted T cells is different to than in functional T cells. This is significant as understanding these gene expression profiles guides the development of checkpoint inhibitors, powerful drugs that act of either cancer cells or T cells to regulate their action.

A number of studies have attempted to uncover the gene expression profiles of both states, such as the 2007 study, published in Immunity, by Dr. Rafi Ahmed’s group at Emory University, which showed that exhausted CD8+ T cells both overexpressed several inhibitory receptors such as cell death protein 1 (PD-1), and displayed significant changes in receptor and cytokine signaling pathways.

Up to today, however, the exact extent of the differences between the exhausted T cell state and the functional state has been unknown.

Now, a new study published in Science attempts to uncover in more depth these genetic differences.

Titled The epigenetic landscape of T cell exhaustion, published by Dr. W. Nicholas Haining at the Dana Farber Cancer Institute and colleagues at the University of Berkeley, uncovered some cues that regulate gene expression in exhausted T-cells.

The authors found that the expression of the PD-1 protein is regulated by a group of genes that includes RAR, T-bet, and Sox3 motifs.  Moreover, the authors uncovered that the differentiation of exhausted T cells occurs alongside regulation of genes which are critical to their dysfunction.

These genes, the authors argue, are suitable targets for genome editing in order to exert tight control of gene expression in exhausted CD8+ T cells, helpful for development of future therapies.

As a preliminary study, the paper outlines a thorough set of data and hypothesis and adds to the growing database of knowledge on the genetic cutes that drive T cells and their function under disease conditions.

Read the full paper here.





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