HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells

Betts, Michael R.; Nason, Martha; West, Sadie M.; Rosa, Stephen C. De; Migueles, Stephen A.; Abraham, Jonathan; Lederman, Michael M.; Benito, José M.; Goepfert, Paul; Connors, Mark; Roederer, Mario; Koup, Richard A.

doi:10.1182/blood-2005-12-4818

Cited by 1,663 publications

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“…Several lines of evidence indicate that the effectiveness of virus-specific immune responses is not only based on the quantity but also on the quality of T cells. 17,20,21 One major finding of our study provides strong evidence that Mes LNs represent major reservoirs not only for animals progressing more rapidly toward AIDS but also in LTNP, in which plasma viral loads were below the level of detection for extended periods of time. The extent of viral replication in the other organs is markedly lower, whereas viral dissemination to non-lymphoid organs appeared only later in the course of SIV infection in macaques of Chinese origin.…”

Section: Discussionmentioning

confidence: 57%

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8 þ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8 þ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-b and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8 þ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8 þ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/ memory CD8 þ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1 þ expressing cells. Finally, we provide evidence that abrogation of TGF-b in vitro enhances T-cell proliferation and reduces CD8 þ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS. Cell Death and Differentiation (2007) 14, 1747-1758; doi:10.1038/sj.cdd.4402192; published online 6 July 2007Virus production in Human Immunodeficiency Virus 1 (HIV-1)-infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection and replication in CD4 þ cells with rapid turnover of both free virus and virus producing cells. Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections. 3 However, most studies, which investigated the potential relationship between HIV and SIV infections and apoptosis have focused on cells from peripheral blood, rather than on cells from lymphoid organs.Peripheral lymphoid tissues such as the axillary and inguinal (Ing) lymph nodes (LNs), which drain the arms and legs, respectively, and the spleen, are considered major sites of HIV/SIV replication. 4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens coul...

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Section: Discussionmentioning

confidence: 57%

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

et al. 2007

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“…generated by these techniques is difficult to analyze and thus computer assistance and mathematical algorithms are absolutely necessary for data interpretation. This problem is enhanced in polychromatic flow cytometry because the analysis is performed on single cells; as a consequence, hundreds of subsets can be identified in a specific cell population and each of them can bear a different function (5,14,15) or play a specific role in the development of diseases (16)(17)(18)(19)(20). A general approach to the visualization of flow cytometric data is the utilization of bivariate plots.…”

Section: Discussionmentioning

confidence: 99%

Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data

et al. 2007

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Background: Polychromatic flow cytometry (PFC) allows the simultaneous determination of multiple antigens in the same cell, resulting in the generation of a high number of subsets. As a consequence, data analysis is the main difficulty with this technology. Here we show the use of cluster analysis (CA) and principal component analyses (PCA) to simplify multicolor data visualization and to allow subjects' classification. Methods: By eight-colour cytofluorimetric analysis, we investigated the T cell compartment in donors of different age (young, middle-aged, and centenarians). T cell subsets were identified by combining positive and negative expression of antigens. The resulting data set was organized into a matrix and subjected to CA and PCA. Results: CA clustered people of different ages on the basis of cytofluorimetric profile. PCA of the cellular subsets identified centenarians within a different cluster from

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“…Both IFN-g À IL-2 1 central memory T cells as well as the so-called multifunctional CD8 1 and CD4 1 T cells simultaneously producing IFN-g, TNF and IL-2 were shown to mediate long-term immunity to Leishmania in mice [35,36]. Recent reports, as reviewed by Makedonas and Betts [37], suggest that multifunctional CD8 1 memory T cells are crucial for disease control in HIV infection [38,39] and polyfunctional CMV-specific CD4 1 and pp65 CD8 1 T cells protect against highlevel replication after liver transplantation [40].Several studies brought new insights into complexity of the CD4 1 [41] and CD8 1 [42,43] T-cell memory, but data on the more detailed analysis of memory T-cell response to EBV are missing.In this study we performed a multiparameter flow cytometry approach to comprehensively analyze the EBV-specific T-cell response in latent infection. Using 15-mer overlapping proteinspanning peptide pools of latent EBNA-1 and lytic BZLF-1 we characterized EBV-specific memory CD4 1 and CD8 1 T cells based on cytokine-producing capability (IL-2, TNF, IFN-g), and differentiation marker expression (CCR7, CD45RA).…”

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confidence: 99%

mentioning

confidence: 99%

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Guerreiro

Letsch

et al. 2010

Eur J Immunol

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EBV infection leads to life-long viral persistence. Although EBV infection can result in chronic disease and malignant transformation, most carriers remain disease-free as a result of effective control by T cells. EBV-specific IFN-c-producing T cells could be demonstrated in acute and chronic infection as well as during latency. Recent studies, however, provide evidence that assessing IFN-c alone is insufficient to assess the quantity and quality of a T-cell response. Using overlapping peptide pools of latent EBV nuclear antigen 1 and lytic BZLF-1 protein and multicolor flow cytometry, we demonstrate that the majority of ex vivo EBV-reactive T cells in healthy virus carriers are indeed IL-2-and/or TNF-producing memory cells, the latter being significantly more frequent in BM. After in vitro expansion, a substantial number of EBV-specific CD4 1 and CD8 1 T cells retained a CC-chemokine receptor 7 (CCR7)-positive memory phenotype. Based on their cytokine profiles, six different EBV-specific T-cell subsets could be distinguished with TNF-single or TNF/IL-2-double producing cells expressing the highest CCR7 levels resembling earlydifferentiated memory T cells. Our study delineates the memory T-cell profile of a protective immune response and provides a basis for analyzing T-cell responses in EBVassociated diseases.Key words: BM . EBV . Immune monitoring . Multifunctional T cells . T-cell memory IntroductionEBV is a human gamma herpesvirus that is widespread in all human populations. Following oral transmission, EBV replicates in the oropharyngeal epithelial cells and infects mucosal B cells, leading to a life-long persistence in the memory B-cell pool [1,2]. The primary infection occurs usually during childhood and is often asymptomatic; however, infection is manifested as acute infectious mononucleosis in a subset of patients [3]. Despite the relatively benign course in most carriers, EBV reactivation is considered as a risk-factor both for malignant transformation and autoimmune diseases. The ability of the EBV encoded protein 1566LMP-1 to induce T-cell-independent immunoglobulin class switch DNA recombination and BAFF, a B-cell activating factor, that rescues self-reactive T cells, is considered to play an important role in the pathogenesis of EBV-related autoimmune and lymphoproliferative disease [4]. EBV is causatively linked to nasopharyngeal carcinoma and B-cell malignant diseases such as endemic Burkitt's lymphoma, Hodgkin's lymphoma and posttransplant lymphoproliferative diseases (PTLD) [5][6][7]. Recent data suggest that EBV is associated with various autoimmune diseases as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and primary Sjögren's syndrome [8,9]. Chronic active EBV infection can also cause Chronic Fatigue Syndrome, which is frequently associated with autoimmune thyreoiditis [10].The EBV cycle has two distinct stages, the latent infection where the genome is maintained at a constant copy number per cell and limited regions of the genome are expressed and the lytic cycle w...

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HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells

Cited by 1,663 publications

References 35 publications

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

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