Séverine Boullier

Regulation by cytokines (IL‐12, IL‐15, IL‐4 and IL‐10) of the Vγ9Vδ2 T cell response to mycobacterial phosphoantigens in responder and anergic HIV‐infected persons

Human Vγ9Vδ2 T cells contribute to immunity against intracellular pathogens and recognize nonpeptidic antigens, such as the mycobacterial phosphoantigen TUBAg. HIV infection is associated with a polyclonal decrease of peripheral Vγ9Vδ2 T cells and we previously reported that the remaining cells show a proliferative anergy to stimulation with Mycobacterium tuberculosis in 60 % of patients. Because of alterations in the Th1/Th2 cytokine balance reported in HIV infection, we analyzed, at the single‐cell level, the influence of exogenous IL‐4, IL‐10, IL‐12 and IL‐15 on the response to mycobacterial phosphoantigens of γ δ T cells from HIV‐infected patients and healthy donors. We report that the strong γ δ T cell response to TUBAg is characterized by the rapid and selective production of the Th1/proinflammatory cytokines IFN‐γ and TNF‐α in responder HIV‐infected donors. In addition, a positive regulation by IL‐12 and IL‐15 of the production of these cytokines by Vγ9Vδ2 T cells in response to nonpeptidic ligands was observed, whereas IL‐4 and IL‐10 had no effect. In contrast, Vγ9Vδ2 T cells from the anergic HIV‐infected donors had lost the ability to produce Th1 cytokines and were not shifted towards a Th2 profile. Furthermore, neither IL‐12 nor IL‐15 could reverse this functional anergy. The consequences of these observations are discussed in the context of HIV pathogenesis.

Phosphoantigen activation induces surface translocation of intracellular CD94/NKG2A class I receptor on CD94− peripheral Vγ9 Vδ2 T cells but not on CD94− thymic or mature γ δ T cell clones

Most adult peripheral blood γ δ T cells express Vγ9/Vδ2‐encoded TCR that recognize a restricted set of nonpeptidic phosphorylated compounds, referred to as phosphoantigens. They also express various MHC class I‐specific inhibitory receptors (IR), in particular CD94/NKG2‐A heterodimers, which participate in the fine tuning of their TCR‐mediated activation threshold. Most mature Vγ9/Vδ2 T cells express surface CD94 receptors, unlike cord blood or thymus‐derived Vγ9/Vδ2 clones, thus suggesting a role for the microenvironment in IR expression. In the present study we show that most CD94− Vγ9Vδ2 PBL ex vivo express an intracellular pool of CD94/NKG2‐A receptors that is translocated to the cell surface upon activation by phosphoantigens or IL‐2. In stark contrast, intracellular CD94/NKG2‐A complexes are undetectable in CD94− thymus or PBL‐derived mature Vδ2 T cell clones, and no surface induction is observed following phosphoantigen activation of T cell clones. Altogether these results provide new insights into the regulation of CD94/NKG2‐A expression on T lymphocytes and suggest the existence of distinct mechanisms controlling in vivo and in vitro induction of IR on these cells.