TLR2 Stimulation Increases Cellular Metabolism in CD8⁺ T Cells and Thereby Enhances CD8⁺ T Cell Activation, Function,...

TLR2 serves as a costimulatory molecule on activated T cells. However, it is unknown how the functionality and antiviral activity of CD8⁺ T cells are modulated by direct TLR2 signaling. In this study, we looked at the TLR2-mediated enhancement of TCR-driven CD8⁺ T cell activation in vitro and in woodchuck hepatitis virus transgenic mice. In vitro stimulation of CD8⁺ T cells purified from C57BL/6 mice showed that TLR2 agonist Pam3CSK4 directly enhanced the TCR-dependent CD8⁺ T cell activation. Transcriptome analysis revealed that TLR2 signaling increased expression of bioenergy metabolism-related genes in CD8⁺ T cells, such as IRF4, leading to improved glycolysis and glutaminolysis. This was associated with the upregulation of genes related to immune regulation and functions such as T-bet and IFN-γ. Glycolysis and glutaminolysis were in turn essential for the TLR2-mediated enhancement of T cell activation. Administration of TLR2 agonist Pam3CSK4 promoted the expansion and functionality of vaccine-primed, Ag-specific CD8⁺ T cells in both wild type and transgenic mice and improved viral suppression. Thus, TLR2 could promote CD8⁺ T cell immunity through regulating the energy metabolism.