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 gamma delta 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: 303319]. Twenty-five years of intense research later this ambivalent view still holds true. Immunologists now appreciate that gamma delta 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 gamma delta T-cell responses, especially with respect to the enigmatic mode of antigen recognition. Here, we portray the peculiar responsiveness of human V gamma 9/V delta 2 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 gamma delta T-cell responses via the recognition of soluble low molecular weight phosphoantigens.