The present project aims at understanding the role of Toll like receptors (TLRs) and regulatory T cells in modulating the anti tumor immunity mediated by γδ T cells in patients with oral and cervical cancer. Preliminary work demonstrated the presence of TLRs (TLR2, TLR3, TLR4 and TLR9) on γδ T cells from freshly isolated peripheral blood leucocytes (PBLs). γδ T cells were immunomagnetically purified from ex-vivo expanded PBLs and stimulated in the presence of a TCR stimulus (IPP and anti-CD3) or a TLR stimulus (Poly I:C) or both in combination.

We are currently interested in analyzing the non-peptidic ligands recognized by γδ T cells on tumor cells. Our studies demonstrate that T lymphocytes expressing the Vγ9/Vδ2 TCR recognize non-peptidic phosphorylated compounds, their synthetic analogs bisphosphonates and endogenous metabolite Isopentenyl pyrophosphate (intermediate metabolite of mevalonate pathway) in tumor cells. γδ T cells release IFN-gamma and TNF-alpha after co-culture with a panel of oral, breast and prostate tumor cell lines as against lowered cytokines in normal, non-transformed cell lines.

γδ T cells play an important role as anti-tumor effector cells. However, their expansion is self-limiting. We investigated the activation induced cell death in γδ T cells after stimulation with heat shock proteins (hsp60, hsp70) that act as ligands for γδ T cells. Characterization of the molecular events in the apoptotic pathway revealed that nitric oxide (NO) is released by γδ T cells after hsp stimulation. Purified γδ T cells when incubated with rhsp60 and rhsp70 as well as artificial NO donors - SNAP and arginine, exhibited changes in mitochondrial membrane potential.