A growing number of pediatric and adult subjects worldwide suffer from impaired immune response to pathogens, due to both disease and medical treatments. Different types of immunodeficiency or immunosuppressive drugs may affect different aspects of the immune system and therefore predispose to different risks of infections (aetiology and severity) that can seriously compromise the survival of patients. In this context, the identification of immune-therapeutic strategies aimed at enhancing innate and adaptive antimicrobial immunity is desirable.

Vγ9Vδ2 T cells constitute a small fraction of T cells in peripheral blood, but exhibit potent, broad, and pleiotropic antiviral activities ranging from direct cytotoxicity of infected cells to the ability to enhance both innate and adaptive immunity of virus-specific αβ T cells. These activities are not virus-specific and can potentially act against virtually any infection. For this reason, Vγ9Vδ2 T cells represent an incredible opportunity in the management of immunocompromised patients who would greatly benefit from improved antimicrobial immunity. The lack of MHC restriction and the easily ex vivo expansion protocols allow to open their possible use in allogeneic context, thus overcoming the obstacle of possible reduced immune function in immunocompromised patients, and offering an “off-the shelves” effective cell therapy.

Moreover, the ability of Vγ9Vδ2 T cells to recognize and kill cells expressing stress antigens may be exploited to optimize strategies based on universal Chimeric Antigen Receptor γδ T cells and/or bispecific γδ T-cell engagers. Finally, the recent data on the use of Vγ9Vδ2-derived-vesicles as therapeutic vectors and effective delivery systems further broaden their possible applications.