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Put this finding on a PILAR

By Amos Esty

Researchers in the lab of Jose Conejo-Garcia, M.D., Ph.D., have found a receptor on T cells that helps to regulate the immune system's response to antigens. The discovery of the receptor, which they named PILAR (proliferation-induced lymphocyte-associated receptor), may have important implications for the development of cancer immunotherapies and the treatment of autoimmune diseases.

T cells play a crucial role in adaptive immunity, but they have to be activated by other cells to become effective. The first step in that process comes when a T cell recognizes an antigen presented by a cell called, logically enough, an antigen-presenting cell (APC). But to ensure that T cells do not respond when they shouldn't—say, when the antigen is produced by the host—it takes a second signal to get the T cell to mount a full defense. If the antigen does, indeed, represent a threat, the APC should express molecules called costimulators, which provide the second signal—the alarm that tells the T cell to proliferate and respond. If costimulators are not present, the T cell should either die or become ineffective.

Antigen: What's interesting about PILAR is that it acts as a costimulator despite being expressed on T cells, not on APCs. Conejo-Garcia calls this discovery "a new paradigm." He found that when some T cells recognize an antigen, they produce PILAR. Once expressed, PILAR can provide the costimulatory signal to a nearby T cell by interacting with another molecule, CD161, activating that T cell. If the neighboring T cell does not express CD161, PILAR causes it to express genes that lead to apoptosis, or cell death.

Conejo-Garcia is curious about the possibilities that the new paradigm, published in the journal Blood, offers for treating cancerous tumors. T cells have the ability to fight off tumors, but only if they recognize tumor cells as a threat. Because tumor cells are similar to regular host cells, APCs often do not provide the costimulatory signal that activates T cells. Conejo-Garcia found that the type of T cells that are most effective against ovarian cancer express PILAR—but usually not CD161. It's possible, he believes, that those T cells could be manipulated to express CD161, thus making them more likely to become activated by their interactions with other T cells that express PILAR.

Target: "Our most interesting direction," Conejo-Garcia says, is investigating how PILAR might affect autoimmunity. A number of autoimmune diseases are caused when helper T cells, which often express PILAR, secrete inflammatory cytokines. So he hypothesizes that by looking for PILAR in inflamed areas, it might be possible to identify—and then target—those cells. Working with other researchers, Conejo-Garcia is now investigating that and other prospects raised by PILAR. As with many findings, it seems that it will take some time to figure out all the discovery's implications.

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