While most killer T cells involved in an immune response die off after they’ve done their work, a few transform into central memory CD8+ T cells (Tcms) to establish lasting immunity. Researchers led by Ludwig Lausanne’s Ping-Chih Ho and Alessio Bevilacqua reported in an August issue of Science Immunology their discovery of a metabolic switch in T cells, PPARβ/δ, that is responsible for this transformation. A master regulator of gene expression, PPARβ/δ is activated in CD8+ T cells as immune responses wind down. The researchers show that T cell exposure to interleukin-15, which is known to support Tcm formation, and expression of a protein named TCF1 engages the PPARβ/δ pathway and helps maintain Tcms. TCF1 expression is a hallmark of a subset of CD8+ T cells—progenitor-exhausted T cells—in tumors that are activated by checkpoint blockade immunotherapy. Ping-Chih, Alessio and colleagues showed that PPARβ/δ is also essential to the formation and maintenance of progenitor-exhausted T cells. Deleting the PPARβ/δ gene from T cells led to the loss of progenitor-exhausted T cells in a mouse model of melanoma. To assess the therapeutic implications of their discovery, the researchers exposed T cells to a molecule that stimulates PPARβ/δ activity and used them to treat mice with melanoma. They showed that the cells delayed tumor growth better than their untreated counterparts, suggesting a metabolic intervention to improve cancer immunotherapy.
PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells
Science Immunology, 2024 August 23