Skewed representation of functionally distinct populations of Vgamma9Vdelta2 T lymphocytes in aging

We recently demonstrated that numerical and functional alterations of gammadelta T cells are present in healthy elderly. Here we observed that the decreased absolute number of Vgamma9Vdelta2 T cells present in old subjects in comparison with young/adult and middle aged donors is due to the reduction of naive and central memory Vgamma9Vdelta2 T cells bearing CD27 and CCR7 antigens. The proportion of effector/memory Vgamma9Vdelta2 T cells lacking CD27 or CCR7 markers was significantly increased in the peripheral blood of old subjects in comparison with younger donors. Moreover, the percentage of CD69+ gammadelta T cells was significantly increased in old subjects in comparison with younger donors after overnight activation, confirming that more effector cells are available in aged people. A functional analysis in young/adult and middle aged donors revealed that effector/memory CD27- Vgamma9Vdelta2 T cells are increased after 10-days of in vitro colture in the presence of isopentenylpyrophosphate (IPP) and IL-2. In contrast, the IPP+IL-2 mediated differentiation and expansion of CD27- effector/memory cells was absent in old subjects, confirming a lack of naive and central memory cells responding to IL-2. Accordingly, the expansion index of effector/memory CD27- Vgamma9Vdelta2 T cells was negatively correlated with the donor age. Finally, terminally differentiated Vgamma9Vdelta2 T cells measured as perforin content after 10-day in vitro expansion showed no age-related difference. These data demonstrated a shift of the circulating gammadelta T cell population towards CD27- and CCR7- effector T cells in the elderly with the reduction of immature CD27+ and CCR7+ T cell precursors.     

Reciprocal alterations of Th1/Th2 function in gammadelta T-cell subsets of human immunodeficiency virus-1-infected patients

While T cells that express Vgamma9 as a variable T-cell receptor chain dominate among peripheral blood gammadelta T cells in healthy adults, Vdelta1 cells are the major subpopulation of gammadelta T cells in human immunodeficiency virus (HIV)-infected patients. We used intracellular cytokine staining and flow cytometry to analyse whether an imbalance of T helper 1 (Th1)/T helper 2 (Th2) cytokine patterns, as observed in alphabeta T cells, also occurs in gammadelta T cells. When compared with healthy HIV-negative subjects, HIV+ patients had a decreased number of interferon-gamma (IFN-gamma)+gammadelta T cells, which showed a linear relation to the CD4+ cell count but not to the plasma viral load. Similar results were obtained when Vgamma9 cells were analysed. In contrast, in the Vdelta1 subpopulation, the number of IFN-gamma+ cells was increased in HIV+ donors when compared with healthy subjects. Even though less impressive, the number of interleukin 4 (IL-4)- and IL-10-producing cells was uniformly inversely correlated with the number of tumour necrosis factor-alpha+ and IFN-gamma+ cells. The increased IFN-gamma-producing capacity of Vdelta1 cells might represent a compensatory mechanism for the progressive loss of Vgamma9 gammadelta T cells during the course of HIV infection.     

Phosphoantigen-reactive Vgamma9Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines.

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.     

Development of Vgamma2Vdelta2+ T cell responses during active mycobacterial coinfection of simian immunodeficiency virus-infected macaques requires control of viral infection and immune competence of CD4+ T cells

Vgamma2Vdelta2+ T cells play a role in antimicrobial responses. It is unknown whether adaptive Vgamma2Vdelta2+ T cell responses during active mycobacterial coinfection of human immunodeficiency virus-infected humans can be generated during effective antiretroviral treatment. Here, simian immunodeficiency virus (SIV)mac-infected macaques previously exposed to bacille Calmette-Guerin (BCG) were reinfected with BCG, were treated either with tenofovir or tenofovir plus indinavir, and were assessed for the development of Vgamma2Vdelta2+ T cell responses during active BCG coinfection. A restored capacity of Vgamma2Vdelta2+ T cells to undergo major expansions and pulmonary migration during active BCG coinfection was detected after simultaneous BCG reinfection and treatment with tenofovir of the SIVmac-infected macaques. Interestingly, a restored expansion of Vgamma2Vdelta2+ T cells in the SIVmac/BCG-coinfected macaques was detectable, even though antiretroviral treatment was initiated 1 month after BCG reinfection. Importantly, the restored expansion of Vgamma2Vdelta2+ T cells coincided with increases in numbers of purified protein derivative-specific interferon- gamma -producing CD4+ T cells and increases in the magnitude of their proliferative responses. In contrast, the SIVmac-infected control macaques exhibited diminished responses of Vgamma2Vdelta2+ T cells and mycobacterium-specific CD4+ T cells during active BCG coinfection. Our results suggest that the development of adaptive immune responses of phosphoantigen-specific Vgamma2Vdelta2+ T cells during active mycobacterium/HIV coinfection requires control of viral infection and immune competence of peptide-specific CD4+ T cells.     

gammadelta T cell subsets in patients with arthritis and chronic neutropenia

BACKGROUND: An abnormal distribution of subsets of gammadelta T cells, which are a component of the inflammatory infiltrate in arthritic synovium, has been demonstrated in the peripheral blood (PB) of patients with arthritis and neutropenia. OBJECTIVE: To evaluate whether the clinical manifestations of patients with arthritis and neutropenia are related to the specific gammadelta T cell subset predominant in the PB. METHODS: Flow cytometry of PB lymphocytes in six consecutive patients with chronic neutropenia and arthritis was performed. Variable (V) gamma and delta gene families were analysed by polymerase chain reaction. cDNA was subjected to direct automated sequencing of T cell receptor (TCR) genes. RESULTS: Three patients had non-deforming and non-erosive rheumatoid factor (RF)(+) polyarticular rheumatoid arthritis, RF(+) oligoarticular arthritis, or RF(-) non-deforming oligoarticular psoriatic arthritis with persistent expansions of Vgamma1(+)/Vdelta2(+), Vgamma2(+)/Vdelta2(+), or Vgamma1(+)/Vdelta (undetermined (2- 1-)) T cells, respectively. The other three patients, without persistent expansion of gammadelta T cells, had either non-deforming and non-erosive oligo- or polyarthritis with a balanced distribution of several Vdelta and Vgamma genes, or severe erosive RF(+) arthritis with deficiency of all but Vgamma1(+)/Vdelta1(+) T cells. CONCLUSIONS: gammadelta T cell lymphoproliferations in chronic neutropenia and arthritis use different Vgamma and Vdelta gene families, often forming T cell receptor (TCR) structures that are infrequent in normal adult PB. Arthritis with Vgamma1(+)/Vdelta2(+), Vgamma2(+)/Vdelta2(+), or Vgamma1(+)/Vdelta2(-)/Vdelta1(-) gammadelta T cells in the PB is non-deforming and non-erosive, suggesting a protective effect of these cells, as opposed to a more pathogenic contribution of Vgamma1(+)/Vdelta1(+) cells.     

Vaccinia virus inhibits T cell receptor-dependent responses by human gammadelta T cells

Vaccinia virus (VV) is an effective vaccine and vector but has evolved multiple mechanisms for evading host immunity. We characterized the interactions of VV (TianTan and New York City Board of Health strains) with human gammadelta T cells because of the role they play in immune control of this virus. Exposure to VV failed to trigger proliferative responses in gammadelta T cells from unprimed individuals, but it was an unexpected finding that VV blocked responses to model antigens by the Vgamma2Vdelta2 T cell subset. Infectious or ultraviolet light-inactivated VV inhibited proliferative Vgamma2Vdelta2 T cell responses to phosphoantigens and tumor cells, prevented cytolysis of Daudi B cells, and reduced cytokine production. Inhibiting Vgamma2Vdelta2 T cells may be a mechanism for evading host immunity and increasing VV virulence. Increased VV replication or expression in the absence of gammadelta T cell responses might contribute to its potency as a vaccine against poxvirus and recombinant antigens.     

HIV-mediated gammadelta T cell depletion is specific for Vgamma2+ cells expressing the Jgamma1.2 segment

Circulating Vgamma2/Vdelta2(+) T cells, normally constituting 3-6% of all CD3(+) T cells in blood, are severely depleted after HIV infection. The mechanism(s) for Vgamma2/Vdelta2(+) T cell depletion are unknown, partly because these cells are CD4(-) and resistant to HIV infection. To determine whether this cell depletion was general for all Vgamma2(+) cells or specific for an individual subset, we analyzed the Vgamma2 repertoire and found consistent differences between HIV(+) and uninfected control samples. The change in Vgamma2 repertoire was the result of preferentially depleting only those Vgamma2 cells that express the Jgamma1.2 segment. The specific loss of Vgamma2-Jgamma1.2(+) cells was polyclonal, as the Vgamma subset retained normal diversity even after HIV infection, and loss occurred without significant changes in the paired chain (Vdelta2) repertoire, or in the alternate Vdelta1 chain repertoire. Specific depletion of Vgamma2-Jgamma1.2/Vdelta2 T cells is the first evidence of a common, T cell receptor-dependent cell loss in HIV disease and it provides a clear example of bystander cell depletion. Vgamma2-Jgamma1.2/Vdelta2 T cells mediate potent responses to microbial pathogens including HIV, and loss of this subset is an important aspect of AIDS pathogenesis.     

Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity

Human peripheral blood gammadelta T cells (Vgamma9(+) Vdelta2(+)) can be selectively expanded in vivo by the systemic administration of aminobisphosphonates without prior antigen priming. To assess the potential of human gammadelta T cells to serve as effector cells of specific anti-tumour immunity, we expanded peripheral blood-derived gammadelta T cells and transduced them with recombinant retrovirus encoding G(D2)- or CD19-specific chimaeric receptors. Flow cytometric analysis of T cells from four individual donors cultured in the presence of zoledronate at day 14 of culture showed selective enrichment of the gammadelta T cell population (Vgamma9(+) Vdelta2(+) CD3(+) CD4(-) CD8(-)) to 73-96% of total CD3(+) T cells. Retroviral gene transfer resulted in chimaeric receptor surface expression in 73 +/- 12% of the population. Transduced gammadelta T cells efficiently recognized antigen-expressing tumour cell targets, as demonstrated by target-specific upregulation of CD69 and secretion of interferon-alpha. Moreover, transduced gammadelta T cells efficiently and specifically lysed the antigen-expressing tumour targets. They could be efficiently expanded in vitro and maintained in culture for prolonged periods. Zoledronate-activated human gammadelta T cells expressing chimaeric receptors may thus serve as potent and specific anti-tumour effector cells. Their responsiveness to stimulation with aminobisphosphonates may enable the selective re-expansion of adoptively transferred T cells in vivo, permitting long lasting anti-tumour immune control.     

Gammadelta T cell activation by chronic HIV infection may contribute to intrahepatic vdelta1 compartmentalization and hepatitis C virus disease progression independent of highly active antiretroviral therapy

HIV and hepatis C virus (HCV) coinfection is frequently associated with rapid progression of HCV-related disease, resulting in a higher risk of cirrhosis. Data suggest that natural T cells expressing the Vdelta1 T cell receptor rearrangement are recruited in the liver of chronically HCV-infected patients and are increased in the peripheral blood of HIV-infected persons. We studied gammadelta T cell distribution in the peripheral blood and liver of HCV-infected and HIV/HCV-coinfected patients in the presence and absence of antiretroviral therapy. We observed that Vdelta1+ T cells releasing helper T cell type 1 cytokines are compartmentalized not only in the liver of HCV+ patients, but also of HIV/HCV-coinfected persons. HIV/HCV patients showed an increased frequency of both peripheral and intrahepatic Vdelta1 natural T lymphocytes, resulting in a higher degree of hepatic inflammation when compared with patients with other liver diseases. Finally, highly active antiretroviral therapy (HAART) was unable to restore Vdelta1T cell circulation to normal levels in chronically HIV-infected persons. We conclude that gammadelta T lymphocytes released from tissue to the bloodstream circulation under the influence of chronic HIV infection may contribute to intrahepatic Vdelta1 compartmentalization and progression of liver disease, independently of HAART.     

Ligand-specific alphabeta and gammadelta T cell responses in childhood tuberculosis

The alphabeta and gammadelta T cell responses were analyzed in the peripheral blood of children affected by active tuberculosis (TB) and in healthy children who tested positive (PPD+) or negative (PPD-) for purified protein derivative. PPD+ healthy and diseased children responded equally well to PPD in vitro. In contrast, only 18% of PPD+ TB patients responded to peptide p38G derived from the 38-kDa protein of Mycobacterium tuberculosis. Analysis of the whole gammadelta T cell population and of its Vgamma9/Vdelta2 subset showed similar frequencies in PPD+ children with TB and in healthy PPD+ and PPD- children. Vgamma9/Vdelta2 cells from children with TB responded to 5 different phosphoantigens similarly to those from healthy PPD+ children, but healthy PPD- children responded very poorly. Chemotherapy had contrasting effects on the tested lymphocyte population, represented by increase of alphabeta and decline of Vgamma9/Vdelta2 T cell responses. T cell responses in childhood TB may be similar to those in adult TB.     

In vitro expansion of gamma delta T cells with anti-myeloma cell activity by Phosphostim and IL-2 in patients with multiple myeloma

T-cell-mediated immunotherapy is a promising therapeutic option for multiple myeloma (MM). Gamma-delta T cells (gammadelta T cells) recognize phosphoantigens and display strong anti-tumour cytotoxicity. The synthetic agonist Phosphostim (bromohydrin pyrophosphate, BrHPP) has been shown to selectively activate Vgamma9Vdelta2 T cells. This study aimed to evaluate the expansion capacity and anti-myeloma cell cytotoxicity of circulating gammadelta T cells from MM patients at different time points throughout the disease, using Phosphostim and interleukin 2 (IL-2). Circulating gammadelta T cell counts in patients with newly diagnosed MM or in relapse did not differ from those in healthy donors. A 14-d culture of peripheral blood mononuclear cells with Phosphostim and IL-2 triggered a 100-fold expansion of gammadelta T cells in 78% of newly diagnosed patients. Gammadelta T cells harvested at the time of haematopoietic progenitor collection or in relapsing patients expanded less efficiently. Expanded gammadelta T cells killed 13/14 myeloma cell lines as well as primary myeloma cells, but not normal CD34 cells. Their killing efficiency was not affected by 2-d IL-2 starvation. This study demonstrated the ability of Phosphostim and IL-2 to expand gammadelta T cells from MM patients, and the efficient and stable killing of human myeloma cells by gd T cells.     

Dynamics of T cells subsets and lymphoproliferative responses during structured treatment interruption cycles and after definitive interruption of HAART in early chronic HIV type-1-infected patients

Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses (LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.     

Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates

Aminobisphosphonates, potent derivatives of bisphosphonates, are frequently used for the treatment of conditions such as osteoporosis and bone metastases that are characterized by excessive osteoclastic bone resorption. Using T-cell receptor (TCR) transfer studies, we show that recognition of antigenic aminobisphosphonates that are known to stimulate human gammadelta T cells in vitro and in vivo (potency: risedronate > alendronate > pamidronate) requires expression of the Vgamma2Vdelta2 TCR and is thus Vgamma2Vdelta2 TCR-dependent. Myeloma cells or monocytes pulsed with risedronate and then washed rendered these target cells sensitive to lysis by a Vgamma2Vdelta2 T-cell clone or cell line. These results suggest that Vgamma2Vdelta2 TCR-dependent recognition leading to direct cytolysis of aminobisphosphonate-sensitized osteoclast or tumor targets may be a mechanism whereby aminobisphosphonate treatment of cancers metastatic to bone decreases osteoclastic activity and tumor burden and also may account for the decreased osteoclastic activity associated with successful treatment of osteoporosis.     

Vdelta2+ gammadelta T cell function in Mycobacterium tuberculosis- and HIV-1-positive patients in the United States and Uganda: application of a whole-blood assay

BACKGROUND: Vgamma9(+)Vdelta2(+) gammadelta T cells (Vdelta 2(+) T cells) are activated by Mycobacterium tuberculosis and secrete interferon (IFN)-gamma. Vdelta 2(+) T cells recognize phosphoantigens, such as bromohydrin pyrophosphate (BrHPP), and link innate and adaptive immunity. METHODS: A whole-blood assay was developed that used IFN-gamma secretion in response to BrHPP as a measurement of Vdelta2(+) T cell function. RESULTS: Peak IFN-gamma levels were detected after stimulating whole blood with BrHPP for 7-9 days. IFN- gamma production in whole blood in response to BrHPP paralleled IFN-gamma production and Vdelta2(+) T cell expansion of peripheral-blood mononuclear cells. The assay was used to evaluate Vdelta2(+) T cell function in subjects in the United States (n = 24) and Uganda (n = 178) who were or were not infected with M. tuberculosis and/or human immunodeficiency virus (HIV) type 1. When 50 micromol/L BrHPP was used, 100% of healthy subjects produced IFN-gamma. The Vdelta2(+) T cell response was independent of the tuberculin skin test response. In Uganda, Vdelta2(+) T cell responses were decreased in patients with tuberculosis (n = 73) compared with responses in household contacts (n = 105). HIV-1-positive household contacts had lower responses than did HIV-1-negative household contacts. HIV-1-positive patients with tuberculosis had the lowest V delta 2(+) T cell responses. CONCLUSIONS: Tuberculosis and HIV-1 infection are associated with decreased Velta2(+) T cell function. Decreased Vdelta2(+) T cell function may contribute to increased risk for tuberculosis in HIV-1-positive patients.     

Selective depression of interferon-gamma and granulysin production with increase of proliferative response by Vgamma9/Vdelta2 T cells in children with tuberculosis

Vgamma9/Vdelta2 T cells can contribute to protective immune response against Mycobacterium tuberculosis, although the extent to which and mechanisms by which they could actually protect against human tuberculosis remain unclear. We have previously reported that Vgamma9/Vdelta2 T cells from tuberculin purified protein derivative (PPD)-positive children, either healthy or affected by different clinical forms of tuberculosis, strongly proliferate to different phosphoantigens in vitro, whereas Vgamma9/Vdelta2 T cells from PPD-negative healthy subjects proliferate very poorly. We report here that Vgamma9/Vdelta2 T cells from tuberculous children have an increased proliferative activity, but decreased interferon (IFN)-gamma production and granulysin expression. After successful chemotherapy, the Vgamma9/Vdelta2 T cell proliferative response strongly decreased, whereas IFN-gamma and granulysin production consistently increased. Disease-associated changes in Vgamma9/Vdelta2 T cell effector functions in patients with tuberculosis are consistent with the possibility that these T cells may play a protective role in immune response against M. tuberculosis infection.     

Alkylamines cause Vgamma9Vdelta2 T-cell activation and proliferation by inhibiting the mevalonate pathway

Three general classes of small, nonpeptide "antigens" activate Vgamma9Vdelta2 T cells: pyrophosphomonoesters, such as isopentenyl diphosphate (IPP), nitrogen-containing bisphosphonates (N-BPs), and alkylamines. However, we have shown recently that N-BPs indirectly activate Vgamma9Vdelta2 T cells as a consequence of inhibition of farnesyl diphosphate synthase (a key enzyme of the mevalonate pathway) and the intracellular accumulation of IPP. We now show that alkylamines activate Vgamma9Vdelta2 T cells by the same mechanism. Alkylamines were found to be weak inhibitors of farnesyl diphosphate synthase and caused accumulation of unprenylated Rap1A in peripheral blood mononuclear cells and macrophages, indicative of inhibition of the mevalonate pathway. Furthermore, as with N-BPs, the stimulatory effect of the alkylamines on Vgamma9Vdelta2T cells was abrogated by simultaneous treatment with mevastatin. These findings suggest that only pyrophosphomonoesters such as IPP are true Vgamma9Vdelta2 T-cell agonists, whereas alkylamines and N-BPs indirectly activate Vgamma9Vdelta2 T cells through a common mechanism involving the accumulation of IPP.     

Phosphoantigen-activated V gamma 2V delta 2 T cells antagonize IL-2-induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Although Foxp3(+) T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated Vgamma2Vdelta2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4(+)CD25(+)Foxp3(+) T cells and subsequent suppression of mycobacterium-driven increases in numbers of Vgamma2Vdelta2 T cells. Surprisingly, activation of Vgamma2Vdelta2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen down-regulated IL-2-induced expansion of CD4(+)CD25(+)Foxp3(+) T cells. Consistently, in vitro activation of Vgamma2Vdelta2 T cells by phosphoantigen plus IL-2 down-regulated IL-2-induced expansion of CD4(+)CD25(+)Foxp3(+) T cells. Interestingly, anti-IFN-gamma-neutralizing antibody, not anti-TGF-beta or anti-IL-4, reduced the ability of activated Vgamma2Vdelta2 T cells to down-regulate Tregs, suggesting that autocrine IFN-gamma and its network contributed to Vgamma2Vdelta2 T cells' antagonizing effects. Furthermore, activation of Vgamma2Vdelta2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFNgamma(+) or perforin(+) Vgamma2Vdelta2 T cells and PPD-specific IFNgamma(+)alphabeta T cells. Thus, phos-phoantigen activation of Vgamma2Vdelta2 T cells antagonizes IL-2-induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection.     

Age-related accumulation of a novel CD44 + CD25lowgammadelta T-cell population in hematopoietic organs of the mouse

We discovered a novel population of gammadelta T cells in the mouse that accumulates with age in hematopoietic organs, but not in epithelia. These cells are CD25low (an unusual phenotype for gammadelta T cells in the mouse); express higher levels of TCRgammadelta and CD44 than do CD25- gammadelta T cells; mainly express Vgamma2, Vgamma3, and Vgamma4 chains; and are largely quiescent. A very similar cell population appears in the late stages of fetal thymus organ cultures, suggesting that the accumulation of CD44 + CD25lowTCRgammadelta + cells is a response to stress induced by aging in vivo or by culture in vitro. The precursors of CD44 + CD25lowTCRgammadelta + cells are generated during fetal or very young adult life, as this population was undetectable in aged recipients of bone marrow from old or young donors. CD44 + CD25lowTCRgammadelta + cells may be a biomarker of aging, but could also play a role in the inflammatory changes that accompany aging.     

Activation of C-C beta-chemokines in human peripheral blood gammadelta T cells by isopentenyl pyrophosphate and regulation by cytokines

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)