Modulation of γδ T cell responses by TLR ligands

Toll-like receptors (TLR) are pattern-recognition receptors that recognize a broad variety of structurally conserved molecules derived from microbes. The recognition of TLR ligands functions as a primary sensor of the innate immune system, leading to subsequent indirect activation of the adaptive immunity as well as none-immune cells. However, TLR are also expressed by several T cell subsets, and the respective ligands can directly modulate their effector functions. The present review summarizes the recent findings of gamma delta T cell modulation by TLR ligands. TLR1/2/6, 3, and 5 ligands can act directly in combination with T cell receptor (TCR) stimulation to enhance cytokine/chemokine production of freshly isolated human gamma delta T cells. In contrast to human gamma delta T cells, murine and bovine gamma delta T cells can directly respond to TLR2 ligands with increased proliferation and cytokine production in a TCR-independent manner. Indirect stimulatory effects on IFN-gamma production of human and murine gamma delta T cells via TLR-ligand activated dendritic cells have been described for TLR2, 3, 4, 7, and 9 ligands. In addition, TLR3 and 7 ligands indirectly increase tumor cell lysis by human gamma delta T cells, whereas ligation of TLR8 abolishes the suppressive activity of human tumor-infiltrating V delta 1 gamma delta T cells on alpha beta T cells and dendritic cells. Taken together, these data suggest that TLR-mediated signals received by gamma delta T cells enhance the initiation of adaptive immune responses during bacterial and viral infection directly or indirectly. Moreover, TLR ligands enhance cytotoxic tumor responses of gamma delta T cells and regulate the suppressive capacity of gamma delta T cells.