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We have compared four human subsets of Vgamma9Vdelta2 T cells, naive (T(naive), CD45RA(+)CD27(+)), central memory (T(CM), CD45RA(-)CD27(+)), effector memory (T(EM), CD45RA(-)CD27(-)) and terminally differentiated (T(EMRA), CD45RA(+)CD27(-)), for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and IL-15R expression were low in T(naive) cells and progressively increased from T(CM) to T(EM) and T(EMRA) cells. In contrast, the capacity to expand in response to antigen or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas antigen-stimulated cells acquired a T(CM) or T(EM) phenotype, IL-15-stimulated cells maintained their phenotype, with the exception of T(CM) cells, which expressed CD27 and CD45RA in various combinations. These results, together with ex vivo bromodeoxyuridine incorporation experiments, show that human Vgamma9Vdelta2 memory T cells have different proliferation and differentiation potentials in vitro and in vivo and that T(EMRA) cells are generated from the T(CM) subset upon homeostatic proliferation in the absence of antigen.

We investigated the interactions between human monocyte-derived dendritic cells (DCs) and Ag-activated circulating TCR-gammadelta-expressing lymphocytes (Vdelta2). Coculture of immature DCs (iDCs) with peripheral blood Vdelta2 T cells activated with either pyrophosphomonoesters (isopentenyl pyrophosphate; IPP) or aminobiphosphonates (pamidronate; PAM) led to a significant up-modulation of CD86 and MHC class I molecules and to the acquisition of functional features typical of activated DCs. DC activation induced by both IPP- and PAM-stimulated gammadelta T cells was mostly mediated by TNF-alpha and IFN-gamma secreted by activated lymphocytes. However, the effect of PAM-activated gammadelta T cells, but not that of IPP-activated cells, required cell-to-cell contact. Reciprocally, activation of Vdelta2 T cells by PAM, but not by IPP, was dependent on cell contact with iDCs. In fact, when PAM-stimulated DC-gammadelta T cell cocultures were separated by a semipermeable membrane or treated with blocking anti-CD86 Abs, induction of CD25 and CD69 as well as IFN-gamma and TNF-alpha secretion by Vdelta2 cells were strongly reduced. These results demonstrate for the first time a bidirectional activating interaction between iDCs and PAM-stimulated gammadelta T lymphocytes, thus suggesting a potential adjuvant role of this early cross-talk in the therapeutic activity of aminobiphosphonate drugs.

Immunity to M.tuberculosis (MTB) infection consists of interactions between various T-cell subsets that control the infection and prevent further reactivation. We analysed the effector/memory T-cell dynamics and cytokines production in the peripheral blood of patients with pulmonary tuberculosis (TB). We observed that the frequency of CD4+ T-cell effectors was significantly increased during active TB, confirming a major role of this T-cell subset in TB immunity. Pre-terminally differentiated CD8+ T-lymphocytes were increased in the peripheral blood as well. In contrast, we observed a reduced number of effector mycobacteria-reactive gammadelta+ T-lymphocytes with a specific defects in reacting to mycobacterial nonpeptidic antigens, suggesting that this innate response is rapidly lost during TB infection. Nevertheless, the frequency of gammadelta+ T-cells effectors in TB patients was higher than the alphabeta+ T-cell response to peptide from MTB-ESAT-6 protein and quantitatively similar to PPD reactivity. Thus, alphabeta+ and gammadelta+ T-cell differentiation and function are differently triggered by active TB infection.

Human gammadelta T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their precise function remains unknown. In adults the major circulating gammadelta T-cell subset expresses the Vgamma9Vdelta2 T-cell receptor and responds to protease-resistant phosphorylated derivatives found in many pathogens. In this study we show that activation of Vdelta2(+) cells with the nonpeptidic antigen isopentenyl pyrophosphate (IPP) rapidly induces (within 4-12 hours) the C-C chemokines MIP-1alpha, MIP-1beta, and lymphotactin but not MCP-1. The most robust response was obtained for MIP-1beta. IPP induction of MIP-1alpha and MIP-1beta was not affected by costimulation with interleukin-4 (IL-4), IL-10, TGF-beta, or interferon-gamma (INF-gamma). However, IL-12 significantly enhanced IPP-induced expression and release of MIP-1alpha that was down-regulated by TGF-beta whereas the induction of MIP-1beta by IPP+IL-12 was refractory to cotreatment with TGFbeta indicating that these chemokines are differentially regulated by these cytokines. Vdelta2(+) T cells also expressed a wide range of C-C chemokine receptors including CCR1, CCR5, and CCR8, all of which were down-regulated following activation. We conclude that Vdelta2(+) cells can be rapidly induced by components of bacterial cell walls to express high levels of proinflammatory chemokines, supporting an important role for these cells in the early stages of the inflammatory responses to many common pathogens. (Blood. 2000, 95:39-47)

The presence of NK receptors (NKR) on populations of T cells has been proposed to play a regulatory role in T cell function, fine tuning the response to Ag, and influencing the nature of the immune response through rapid secretion of large amounts of cytokines. In this study, we assessed the nature and distribution of NKR on human peripheral blood gamma delta T cells and established clones to study cytokine release. In circulating gamma delta T cells, approximately 80% expressed CD94, approximately 25% expressed NKR-P1A, and approximately 20% expressed p58, values substantially higher than those found on alpha beta T cells from the same donors. When cloned for specific NKR expression, most cells in culture were NKR-P1A+ whereas p58 expression was variable, suggesting that the NKR-P1A phenotype can be acquired in culture whereas expression of p58 is more stable. Some clones were triple positive for CD94, NKR-P1A, and p58. V delta 2+ cells generally expressed a wider range of NKR than V delta 1+ cells. Following activation through CD3, all gamma delta T cell clones released large amounts of IFN-gamma, commencing as early as 4 h postactivation. Some clones also released TNF-alpha and IL-4, but no correlation with specific NKR expression was noted. Activation through NKR-P1A induced moderate levels of IFN-gamma without inducing IL-4. The results suggest that activation of most gamma delta T cells is regulated by signaling events occurring via both the TCR and the NKR. They further show that peripheral blood gamma delta T cells may function as a source of the proinflammatory cytokines IFN-gamma and TNF-alpha.

Lethally irradiated mice were grafted with syngeneic bone marrow cells or left ungrafted. Mice of each group were injected with different hematopoietic cytokines for 5 consecutive days starting immediately after irradiation or left uninjected. The recovery of lymphoid tissues induced by hematopoietic cytokines 7 days after irradiation and bone marrow cell transplantation was comparable to that observed at days 21–28 in irradiated, bone marrow-grafted, but cytokine-uninjected mice. IL-11 or IL-6, in combination with IL-3, was able to hasten thymus, spleen and blood cell numbers and functions. SCF also displayed a detectable effect when used with IL-3. Conversely, the IL-6 super-agonist K-7/D-6 was able, when injected alone, to induce significant recovery of thymus, spleen and blood cells. Thus, K-7/D-6 appears to be a most efficient cytokine for fast reconstitution of lymphoid tissues after irradiation and bone marrow transplantation. Bone Marrow Transplantation (2000) 25, 427–433. [ABSTRACT FROM AUTHOR]

Vgamma9Vdelta2 T lymphocytes are broadly reactive against various intracellular pathogens and display both lytic and proliferative responses to human immunodeficiency virus (HIV)-infected cells. HIV infection of peripheral blood mononuclear cell cultures led to absolute increases in Vgamma9Vdelta2 T cells accompanied by decreased p24 levels. Strong gammadelta T cell activation with nonpeptidic mycobacterial phosphoantigens (TUBAg1 extract or synthetic isopentenyl pyrophosphate) resulted in potent inhibition of HIV replication through soluble released factors. Subsequent analyses showed that phosphoantigen-activated gammadelta T cells produced substantial amounts of beta-chemokines (macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and regulated-on-activation, normal T-cell-expressed and -secreted beta-chemokine [RANTES]), which represent the natural ligand for the CCR5 HIV coreceptor. Accordingly, anti-beta-chemokine antibodies neutralized the inhibition of monocytotropic HIV strains by gammadelta T cell-released factors. Moreover, a T-tropic HIV strain using the CXCR4 coreceptor for virus entry was potently inhibited. Together, these data reveal that phosphoantigen-activated gammadelta T cells are an important source of CC chemokines and may suppress HIV replication through cell-released antiviral factors. [ABSTRACT FROM AUTHOR]