HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression.

Stefanová, I; Saville, M. Wayne; Peters, Christian; Cleghorn, Farley; Schwartz, Daniella M.; Venzon, David; Weinhold, Kent J.; Jack, Noreen; Bartholomew, Courtenay; Blattner, W. A.; Yarchoan, Robert; Bolen, Joseph B.; Horak, Ivan D.

doi:10.1172/jci118915

Cited by 83 publications

(79 citation statements)

References 52 publications

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“…Consistent with this idea, peripheral CD8 ϩ T cells in HIV-1-infected patients display a phenotype of chronic activation and reduced function (43)(44)(45)(46)(47). As the thymus is the source of naive T cell emigrants that replenishes depleted peripheral pools, its output could be pivotal in maintaining suppression of HIV-1 viral infection.…”

Section: Discussionmentioning

confidence: 65%

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Keir

Rosenberg

Sandberg

et al. 2002

The Journal of Immunology

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Infection with the HIV type 1 (HIV-1) can result both in depletion of CD4+ T cells and in the generation of dysfunctional CD8+ T cells. In HIV-1-infected children, repopulation of the peripheral T cell pool is mediated by the thymus, which is itself susceptible to HIV-1 infection. Previous work has shown that MHC class I (MHC I) molecules are strongly up-regulated as result of IFN-α secretion in the HIV-1-infected thymus. We demonstrate in this study that increased MHC I up-regulation on thymic epithelial cells and double-positive CD3−/intCD4+CD8+ thymocytes correlates with the generation of mature single-positive CD4−CD8+ thymocytes that have low expression of CD8. Treatment of HIV-1-infected thymus with highly active antiretroviral therapy normalizes MHC I expression and surface CD8 expression on such CD4−CD8+ thymocytes. In pediatric patients with possible HIV-1 infection of the thymus, a low CD3 percentage in the peripheral circulation is also associated with a CD8low phenotype on circulating CD3+CD8+ T cells. Furthermore, CD8low peripheral T cells from these HIV-1+ pediatric patients are less responsive to stimulation by Ags from CMV. These data indicate that IFN-α-mediated MHC I up-regulation on thymic epithelial cells may lead to high avidity interactions with developing double-positive thymocytes and drive the selection of dysfunctional CD3+CD8low T cells. We suggest that this HIV-1-initiated selection process may contribute to the generation of dysfunctional CD8+ T cells in HIV-1-infected patients.

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Section: Discussionmentioning

confidence: 65%

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Keir

Rosenberg

Sandberg

et al. 2002

The Journal of Immunology

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“…The decreased expression of the TCR -chain is not only observed in the hyporesponsive SF T lymphocytes from RA patients but also in tumor-infiltrating T lymphocytes from human cancer patients and in the hyporesponsive T lymphocytes from HIV-infected individuals. In all cases, only the expression of the TCR -chain is reduced, while the expression of other components of the TCR/CD3 complex remains constant (30,31,(37)(38)(39). Although the correlation between the hyporesponsive state of the T lymphocytes and the reduced TCR expression suggests a causal relationship, formal evidence for this hypothesis is not available.…”

Section: Discussionmentioning

confidence: 97%

Displacement of Linker for Activation of T Cells from the Plasma Membrane Due to Redox Balance Alterations Results in Hyporesponsiveness of Synovial Fluid T Lymphocytes in Rheumatoid Arthritis

Gringhuis

Leow

Voort

et al. 2000

The Journal of Immunology

126

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The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by ζ-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l-cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress.

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“…While patients' T cells may recover expression of z in part during ex vivo stimulation with anti-CD3 mAb, z remained low at 24 or 48 h of culture relative to its expression in normal T cells incubated in parallel. Downregulation of z expression has been reported in T and NK cells of patients with cancers (Zea et al, 1995;Rabinowich et al, 1996Rabinowich et al, , 1998Reichert et al, 1998a, b;Kiessling et al, 1999;Kuss et al, 1999;Whiteside, 1999Meidenbauer et al, 2002;Reichert et al, 2002) and with chronic infections, including HIV (Stefanova et al, 1996;Zea et al, 1998). A transient loss of z expression appears to be a normal consequence of signalling via TcR (Valiutti et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

“…A transient loss of z expression appears to be a normal consequence of signalling via TcR (Valiutti et al, 1997). However, in patients with cancer or chronic infections such as leprosy or HIV, z expression may never recover to equal that in normal T cells (Stefanova et al, 1996;Zea et al, 1998), and its absence or partial loss in cancer patients appears to be substantially more common in tumour-infiltrating than in circulating T lymphocytes (Otsuji et al, 1996). Several different mechanisms have been proposed to explain the loss of z expression, including production of reactive oxygen metabolites (ROM) by tumour or tumour-associated monocytes (Kono et al, 1996;Otsuji et al, 1996), or by circulating activated granulocytes (Schmielau and Finn, 2001); apoptosis in the tumour microenvironment (Gastman et al, 1999;Hoffmann et al, 2002;; production and release by the tumour of z inhibitory proteins (Taylor et al, 2001); the availability of L-arginine in the microenvironment (Taheri et al, 2001) or increased degradation of z in chronically activated T cells (Penna et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck

et al. 2003

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A subset of circulating T cells (CD8 + CD45RO À CD27 À ) with a naïve phenotype, but mediating effector function, is considered to play an important role in host antitumour defence. To investigate the attributes of these effector T cells in patients with squamous cell carcinoma (SCC) of the head and neck cancer, venous blood was obtained from 39 individuals with cancer and 45 normal controls (NC). Peripheral blood mononuclear cells were isolated, stained with labelled monoclonal antibodies specific for CD8, CD45RO, CD45RA, CD62L, CD27, TCR-z as well as isotype controls and examined by multicolour flow cytometry. Annexin V binding to CD8 + T cells and PMA/ionomycin-induced IFN-g expression were also evaluated in patients and NC. The proportions of CD45RA + CD45RO À (naïve) and CD45RA À CD45RO + (memory) cells were found to be comparable within the CD8 + T-cell subset. However, relative to NC, the frequency of effector CD8 + CD45RO À CD27 À cells was strikingly increased in all SCC patients regardless of the disease status (P ¼ 0.0003). The proportion of these cells was found to increase with age in both patients and NC. In NC, stimulated IFN-g expression was largely restricted to CD8 + CD45RO À CD27 + cells, while in patients CD8 + CD45RO À CD27 À expressed IFN-g after ex vivo stimulation. Expression of the TCR-associated z chain was decreased or absent in freshly isolated CD8 + CD45RO À CD27 À T cells in patients (Po0.0001). Annexin V was found to bind to a higher proportion of circulating CD8 + T cells in patients than NC (Po0.006), and significantly more Annexin V + T cells were present in the effector (Po0.0059) than the naïve subset within the CD8 + CD45RO À compartment. The data indicate that the expanded CD8 + CD45RO À CD27 À T cells, which contain precursors of IFN-g-producing T cells, are z-negative and sensitive to apoptosis in the circulation of patients with HNC.

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HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression.

Abstract: In attempt to elucidate the mechanism of the HIV infection induced T cell unresponsiveness, we studied signal-transducing molecules proximal to the T cell receptor (

Cited by 83 publications

References 52 publications

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus

Displacement of Linker for Activation of T Cells from the Plasma Membrane Due to Redox Balance Alterations Results in Hyporesponsiveness of Synovial Fluid T Lymphocytes in Rheumatoid Arthritis

Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck

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