Human γδ T-cell responses in infection and immunotherapy: Common mechanisms, common mediators?

Upon receiving the Nobel Prize in Physiology or Medicine in 1987, Susumu Tonegawa referred to the then recent discovery of the γδ T-cell receptor and stated that "while the function of the T cells bearing this receptor is currently unknown (…) these T cells may be involved in an entirely new aspect of immunity". [Tonegawa, S., Scand. J. Immunol. 1993. 38: 303-319]. Twenty-five years of intense research later this ambivalent view still holds true. Immunologists now appreciate that γδ T cells indeed represent a highly intriguing "new aspect of immunity" that is unique and distinct from conventional lymphocytes, yet even scientists in the field still struggle to understand the molecular basis of γδ T-cell responses, especially with respect to the enigmatic mode of antigen recognition. Here, we portray the peculiar responsiveness of human Vγ9/Vδ2 T cells to microorganisms, tumor cells and aminobisphosphonates, in an attempt to integrate the corresponding - and at times confusing - findings into a "theory of everything" that may help explain how such diverse stimuli result in similar γδ T-cell responses via the recognition of soluble low molecular weight phosphoantigens.