γδ T‐cell anergy in human immunodeficiency virus‐infected persons with opportunistic infections and recovery after highly active antiretroviral therapy

Human Vγ9Vδ2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vγ9Vδ2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vγ9Vδ2 T cell activities may be clinically beneficial. The functional characteristics of Vγ9Vδ2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 × 105 U/animal) IL-2 induces a large pool of CD27+ and CD27− effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only γδ (but not αβ) T cells expressed the CD69 activation marker, indicating that Vγ9Vδ2 T lymphocytes are more responsive to low-dose IL-2 than αβ T cells. Up to 100-fold increases in the numbers of peripheral blood Vγ9Vδ2 T cells were observed in animals receiving the γδ stimulatory drug plus IL-2. Moreover, the expanded Vγ9Vδ2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-γ. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.

Section: Discussionmentioning

confidence: 99%

Drug-Induced Expansion and Differentiation of Vγ9Vδ2 T Cells In Vivo: The Role of Exogenous IL-2

Casetti

Perretta

Taglioni

et al. 2005

“…The expansion of V␥9V␦2 ϩ T cells after 10 days of culture was determined by cytometric analysis using double staining with anti-CD3 and anti-TCR-V␦2 mAbs coupled to PE or FITC, respectively. V␦2 expansion index was calculated dividing the absolute number of V␦2 ϩ T cells in stimulated cultures by the absolute number of V␦2 ϩ T cells in unstimulated cultures (20,21). The IPP-driven PBMC proliferation assay was performed in triplicate in 96-well flat-bottom plates with 2.5 ϫ 10 5 PBMC/ml in 0.2 ml containing 5 U/ml rIL-2 with or without 100 M IPP.…”

Section: Cell Preparation and Stimulationmentioning

confidence: 99%

Lack of CD27−CD45RA−Vγ9Vδ2+ T Cell Effectors in Immunocompromised Hosts and During Active Pulmonary Tuberculosis

Gioia

Agrati

Casetti

et al. 2002

101

112

In humans, the circulating pool of mycobacteria-reactive Vγ9Vδ2+ T cells is expanded with age and may contribute to Mycobacterium tuberculosis immunosurveillance. We observed that two subsets of Vγ9Vδ2+ T cells could be identified on the basis of CD27 expression in immunocompetent adults, showing that functionally differentiated γδ T cells have lost CD27 expression. In contrast, the CD27−CD45RA−Vγ9Vδ2+ T cell subset of effector cells was absent in cord blood cells from healthy newborns and lacking in the peripheral blood from HIV-infected patients. Moreover, circulating Vγ9Vδ2+ T cell effectors were significantly reduced in patients with acute pulmonary tuberculosis, resulting in a reduced frequency of IFN-γ-producing cells after stimulation with nonpeptidic mycobacterial ligands. These observations indicate that monitoring and boosting γδ T cell effectors could be clinically relevant both in immunocompromised hosts and during active tuberculosis disease.

“…It has clearly been shown that T cell anergy is present in HIV-infected patients with opportunistic infections (31) and that HIV infection-induced defective IL-2 production in T cells can be partially restored by highly active antiretroviral therapy (32). Other studies showed that anergy in T cells can be induced by HIV-1 proteins gp120 (33) and Env (34) and can be reversed by IL-2 (35,36).…”

Section: Discussionmentioning

confidence: 99%

CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys Produce More IL-2 Than Cells from Disease-Susceptible Species: Involvement of p300 and CREB at the Proximal IL-2 Promoter in IL-2 Up-Regulation

Boštík

Noble

Stephenson

et al. 2007

IL-2 is an important cytokine required for the physiological function of CD4+ T cells. Immunological unresponsiveness—anergy— of CD4+ T cells is characterized by the inability of these cells to synthesize IL-2. Both progressive HIV infection leading to AIDS in humans and SIV infection in rhesus macaques (RM) are associated with dysregulation of IL-2 synthesis. In certain nonhuman primate species, such as sooty mangabeys (SM), SIV infection does not lead to AIDS. We have shown that this is associated with the resistance of the CD4+ T cells from SM to undergo anergy in vitro. In this study, we show that CD4+ T cells from SM spontaneously synthesize 2- to 3-fold higher levels of IL-2 than corresponding cells from RM. Proximal IL-2 promoter constructs derived from SM show significantly higher activity than the RM-derived constructs in primary CD4+ T cells, which is associated with an element at approximately nt −200. Activity of both constructs was up-regulated by p300 and down-regulated by CREB to a similar degree. Chromatin immunoprecipitation analysis showed significantly higher binding of p300 and lower binding of CREB to the SM promoter in vivo. Two single nucleotide substitutions present in the SM sequence around position −200 and −180 seem to increase the affinity of these sites for the binding of transcription factors, one of which was identified as Oct-1. These unique characteristics of the proximal IL-2 promoter in SM therefore can represent one of the mechanisms contributing to the resistance of these cells to undergo anergy.