Sensing the enemy within: Vγ9Vδ2 T cells as metabolic sensors of intracellular parasites.

V gamma 9 V delta 2 (Vγ9Vδ2) T cells, the predominant γδ T cell population in human peripheral blood, uniquely recognize nonpeptidic phosphoantigens (pAgs) independent of major histocompatibility complex molecules. This sensing mechanism relies on intracellular pAg accumulation, which triggers heteromeric cooperation between transmembrane butyrophilin 3A1 (BTN3A1) and butyrophilin 2A1 (BTN2A1) receptors to activate the γδ T cell receptor. This review synthesizes current knowledge of Vγ9Vδ2 T cell immunobiology, focusing on responses to Plasmodium falciparum and Toxoplasma gondii. We examine how these cells detect parasite- or host-derived pAgs to drive rapid cytotoxicity and interferon gamma production. Understanding these sensing mechanisms offers novel insights for harnessing γδ T cells in antiparasitic therapies and vaccine design.