Researchers led by Jose Conejo-Garcia of Dartmouth Medical School recently discovered a new modulator of human T-cell expansion. The molecule, which they named PILAR, may have applications in the treatment of autoimmune diseases and anti-cancer therapies. The finding was published last August in the journal Blood.
PILAR (proliferation-induced lymphocyte-associated receptor) is a human trans-membrane molecule found on chromosome 12. The molecule acts as a costimulator in the immune response.
“We were interested in finding receptors of immune cells similar to NKG2D [costimulators naturally expressed by T cells] and we actually isolated four or five molecules initially. But since we were only interested in those stimulator molecules that act on T cells, only PILAR stood out among the molecules,” Conejo-Garcia said.
When the immune system detects a foreign antigen, a first signal response stimulates T cell proliferation. As a costimulator, PILAR acts as the second signal that continues T cell expansion, thus preventing the apoptosis (cell suicide) of T cells that normally follow the first signal.
Specifically, PILAR signaling through CD161 (a molecule in humans that is expressed by memory T cells and some natural killer cells) increases the expression of molecules that block apoptosis, and induces secretion of T helper type 1 cytokines (regulatory proteins that act as intercellular mediators in the immune response).
However, when CD161 is blocked, PILAR is found to induce apoptotic death on naïve and early-activated T cells within 24 hours. Thus, depending on the receptor expressed at different states of T cell activation, PILAR either increases or decreases T cell survival.
It was also found that PILAR is up-regulated in activated T cells and boosts robust T cell proliferation. It was expressed in around 10 percent of CD4 T cells in two samples of inflammatory synovial fluid, “suggesting a potential role in the pathogenesis of joint inflammation,” according to the article. Ongoing research may determine the level of PILAR involvement in autoimmune diseases.
Furthermore, PILAR, but not CD161, was found to be expressed in ovarian cancer-infiltrating CD4 and CD8 T cells.
“Where do we go from here? We hope to explore further the role of PILAR in inflammation, and how blocking and down-regulating PILAR may prevent or at least reduce inflammation. Also, it may be a good additional costimulator to be explored in anticancer therapies. We are crossing our fingers,” Conejo-Garcia said.