LA JOLLA, CA—According to new research in the journal Immunity, T cells have a nuclear receptor doing something very odd—but very important—to help them fight pathogens and destroy cancer cells. This receptor, called retinoic acid receptor alpha (RARα), is known to control gene expression programs in the nucleus, but it also now appears to operate outside the cell nucleus to coordinate the early events triggered at the cell surface that lead to T cell activation.
Scientists wouldn't normally expect to see a nuclear receptor such as RARα playing this role outside the cell nucleus. And yet the new findings suggest T cells cannot begin to fight disease without a form of RARα on the scene in the cytoplasm.
"Cytoplasmic retinoic acid receptors turn out to be central for a T cell to link sensing at the cell surface with downstream signaling cascades and gene expression programs that transform the T cell to become an active fighter," says Professor Hilde Cheroutre, Ph.D., who led the new study at La Jolla Institute for Immunology (LJI) with LJI Assistant Professor Samuel Myers, Ph.D., LJI Professor Mitchell Kronenberg, Ph.D., and LJI Professor Emeritus Amnon Altman, Ph.D.
The study is also the result of a successful collaboration with scientists at the RIKEN Center for Integrative Medical Sciences in Japan and local teams at UC San Diego and the Salk Institute.
Helping T cells respond to danger
To understand this finding, it helps to picture the geography of a T cell. The cell nucleus (with its bundled-up DNA) sits in the middle of the cell. Other molecules and cellular structures called organelles float in the cytoplasm outside the nucleus surrounded by a membrane at the border of the cell (cell membrane).
Special molecules called T cell receptors (TCRs) sit on the cell membrane, where they receive messages from other cells. You can imagine TCRs as fire-spotters, the lookouts who scan for smoke from remote cabins in the wilderness. Just as fire-spotters need to alert officials to any smoke in the distance, TCRs need to quickly signal headquarters—the cell nucleus—if they detect a potential threat, such as a virus or cancer cell.
Sending that signal to the cell nucleus is critical for activating gene expression to transform the T cell to a fighter cell. But TCRs can't just pick up a phone, so how do they alert the distant cell nucleus to trouble?
