Differential activation of human gamma delta cells by nonpeptide phosphoantigens

Human T cells expressing V gamma9/V delta2-encoded TCR recognize several no npeptide phosphoantigens in the absence of major histocompatibility complex restriction. As these cells respond differentially to increasing concentra tions of structurally related phosphoantigens, such ligands constitute agon ists of different strengths. By analyzing early cellular events and late ef fector responses of y delta T cells, we compared their patterns of stimulat ion by weak, medium and strong phosphoantigen agonists. We found that, alth ough the early metabolic activation as assessed by cytosensor microphysiome try directly reflects the intensity of subsequent effector response by y de lta cells, TCR down-modulation is dissociated from the latter. Weak and mid -range phosphoantigen agonists induce a time- and dose-dependent downmodula tion of the y delta TCR, whereas strong phosphoantigen agonists induce litt le or no TCR down-regulation. This indicates that y delta TCR down-modulati on does not match the extent of TCR signaling as assessed by microphysiomet ry or conventional effector responses (TNF-alpha production and cytotoxicit y). This differential pattern of y delta cell activation by phosphoantigens could explain the stronger potencies of some of these agonists.