Haematopoietic stem cells are maintained in a multipotent state via an important signaling pathway called Wnt, but the role of Wnt signaling in differentiated or mature blood cells is less clear. In a recent study published in Nature Medicine, Nicholas Restifo and colleagues at the National Cancer Institute, a part of the National Institutes of Health in Bethesda, Maryland, reported that Wnt signaling in a subset of mature T lymphocytes called CD8+ T cells promotes the generation of stem-like memory CD8+ T cells that have antitumour activity1. What's more, this population of stem-like cells seems to hold promise for anticancer immunotherapy.

The researchers isolated mature T lymphocytes from mice and stimulated them with antigen, priming these cells to launch an attack. If treated with a Wnt activator, however, these lymphocytes differentiated less and proliferated more.

These data suggest that Wnt function is not restricted to haematopoietic stem cells (HSCs), says Restifo, and represent the first demonstration of Wnt function in mature T lymphocytes. The authors also observed that these T lymphocytes adopt stem-like and memory properties: when Wnt signalling was activated in mice, these cells maintained their ability for self-renewal and multipotency following multiple cell divisions, re-isolation and re-transplantation compared with other T cells.

According to Randall Moon, director of the Institute for Stem Cell and Regenerative Medicine at the University of Washington School of Medicine in Seattle, Wnt signaling is thought to maintain HSCs in a self-renewing and undifferentiated state, making Restifo's findings "quite interesting" and therapeutically important. However, because Wnt signaling activation has been shown to be tumourigenic in several settings, Moon cautions that the homeostatic levels of Wnt signaling in mediating stem cell proliferation must be carefully balanced and controlled to avoid potential cancer initiation when used in a therapeutic setting.

Although the mechanisms of these events are not fully understood, one possible explanation may be gleaned from the observation that Wnt signaling suppressed Eomesodermin, a master regulator of CD8+ T cell differentiation. Whether reduced Eomesodermin expression keeps these T cells in a naïve state would require further investigation. Furthermore, Restifo's group is currently addressing the questions of whether these stem-like CD8+ T cells occur naturally and how these cells actually get Wnt signals during their development or maintenance.

When administered together with tumour antigen vaccination and the immune system stimulant IL-2, these stem-like memory CD8+ T cells were effective in destroying bulky tumours and improving the survival of treated mice compared with other types of memory T cells. Moon believes that this paper offers the most compelling model for using Wnt therapeutically for a variety of diseases. Accordingly, Restifo's group is currently generating tumour-specific human memory stem-like T cells for use in cancer immunotherapy, and they hope to extend this approach to the treatment of infectious diseases like HIV or chronic hepatitis in the future.