Important Immune Cell Regulators’ Response Identified

The technology may also be used to identify the genes that underlie tumor cell development.

There are approximately 40,000 genes in each of the body’s cells, but functions for only approximately 505 of them are known. The conventional approach to determine the function of individual genes is time-consuming. “Typically, studies to identify differentiation players are done one gene at a time,” said Associate Professor Matthew Pipkin of TSRI, who led the study with Prof. Shane Crotty of the La Jolla Institute for Allergy and Immunology (La Jolla, CA, USA). “Our study describes a novel method that can ‘screen’ entire gene families to discover the functions of a large number of individual genes simultaneously, a far more efficient methodology.”

In the new study, published August 23, 2014, in the journal Immunity, the scientists studied genes that control the specialization of T cells into effector cells that eliminate pathogens during infection and “memory” cells that survive long term to maintain guard after the first infection has gone, keeping the same pathogens from re-infecting the body after it has battled them off once.

In their research, the investigators created a mixture of T cells, identical except that the expression of a different gene was interrupted in each cell so the pool of cells represented disruption of a large set of genes. The researchers then assessed the cells’ response to Lymphocytic choriomeningitis virus (LCMV). Before-and-after-infection studies revealed which cells with interrupted genes had emerged after infection; cells in which disruption of a specific gene resulted in it being lost from the mixture indicated the gene played a role in promoting the cell's development into an antiviral T cell.

The study effectively detected two earlier unidentified factors that work together during T cell differentiation—cyclin T1 and its catalytic partner Cdk9, which together form the transcription elongation factor (P-TEFb). While widely expressed throughout the body and used in a number of developmental processes, the factors were previously unknown to be important in the differentiation of both antiviral CD4 and CD8 T cells.

“One of the regulators we uncovered normally enhances effector T cell differentiation at the expense of generating memory T cells and T cells that orchestrate antibody production,” Prof. Pipkin said. “That’s one candidate that you'd want to 'turn down' if you wanted to create more T cells that form memory cells and promote a more effective antibody response—something that would be extremely helpful in developing a vaccine.”

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La Jolla Institute for Allergy and Immunology