The Co-Stimulatory Effects of MyD88-Dependent Toll-Like Receptor Signaling on Activation of Murine [gamma][delta] T Cells

[gamma][delta] T cells express several different toll-like receptor (TLR)s. The role of MyD88- dependent TLR signaling in TCR activation of murine [gamma][delta] T cells is incompletely defined. Here, we report that Pam3CSK4 (PAM, TLR2 agonist) and CL097 (TLR7 agonist), but not lipopolysaccharide (TLR4 agonist), increased CD69 expression and Th1-type cytokine production upon anti-CD3 stimulation of [gamma][delta] T cells from young adult mice (6-to 10-week-old). However, these agonists alone did not induce [gamma][delta] T cell activation. Additionally, we noted that neither PAM nor CL097 synergized with anti-CD3 in inducing CD69 expression on [gamma][delta] T cells of aged mice (21-to 22-month-old). Compared to young [gamma][delta] T cells, PAM and CL097 increased Th-1 type cytokine production with a lower magnitude from anti-CD3- stimulated, aged [gamma][delta] T cells. V[gamma]1.sup.+ and V[gamma]4.sup.+ cells are two subpopulations of splenic [gamma][delta] T cells. PAM had similar effects in anti-CD3-activated control and V[gamma]4.sup.+ subset- depleted [gamma][delta] T cells; whereas CL097 induced more IFN-[gamma] production from V[gamma]4.sup.+ subset-depleted [gamma][delta] T cells than from the control group. Finally, we studied the role of MyD88-dependent TLRs in [gamma][delta] T cell activation during West Nile virus (WNV) infection. [gamma][delta] T cell, in particular, V[gamma]1.sup.+ subset expansion was significantly reduced in both MyD88- and TLR7- deficient mice. Treatment with TLR7 agonist induced more V[gamma]1.sup.+ cell expansion in wild-type mice during WNV infection. In summary, these results suggest that MyD88-dependent TLRs provide co-stimulatory signals during TCR activation of [gamma][delta] T cells and these have differential effects on distinct subsets.