Infection of CD127+(Interleukin-7 Receptor+) CD4+Cells and Overexpression of CTLA-4 Are Linked to Loss of Antigen-Specific CD4 T Cells during Primary Human Immunodeficiency Virus Type 1 Infection

Zaunders, John; Ip, Susanna; Munier, C. Mee Ling; Kaufmann, Daniel E.; Suzuki, Kazuo; Brereton, Choechoe; Sasson, Sarah C.; Seddiki, Nabila; Koelsch, Kersten K.; Landay, Alan; Grey, Pat; Finlayson, Robert; Kaldor, John; Rosenberg, Eric S.; Walker, Bruce D.; Groth, Barbara Fazekas de St; Cooper, David A.; Kelleher, Anthony D.

doi:10.1128/jvi.00249-06

Cited by 78 publications

(92 citation statements)

References 101 publications

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“…Accumulation of CD152-expressing cells in mesenteric lymph nodes as described in HIV and SIV infection (Andersson et al, 2005;Estes et al, 2006;Karlsson et al, 2007;Nilsson et al, 2006;Zaunders et al, 2006) was monitored in the SHIV 89.6p -infected animals at the end of the study (week 40 p.i.). Although at this time point expression was low on peripheral blood T cells, high numbers of CD152-expressing CD4 + T cells were seen in the lymphoid tissues.…”

Section: Zaundersmentioning

confidence: 99%

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

Koopman

Mortier

Hofman

et al. 2009

Journal of General Virology

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Human immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV)infection in macaques are accompanied by a combined early loss of CCR5 (CD195)-expressing CD4 + memory T cells, loss of T-helper function and T-cell hyperactivation, which have all been associated with development of high virus load and disease progression. Here, a cohort of vaccinated simian-human immunodeficiency virus strain 89.6p (SHIV 89.6p )-infected rhesus macaques, where preferential depletion of these memory T-cell subsets does not take place and CD4 + T cells are relatively well maintained, was used to study the role of hyperactivation as an independent factor in the establishment of set-point virus load. In the acute phase of the infection, a transient loss of CD4 + T cells, as well as strong increases in expression of proliferation and activation markers on CD4 + and CD8 + T cells, together with CD152 expression on CD4 + T cells, were observed. Peak expression levels of these markers on CD4 + T cells, but not on CD8 + T cells, were correlated with high virus replication in the chronic phase of the infection. In addition, the peak expression level of these markers was correlated inversely with acute-phase, but not chronic-phase, HIV/SIV-specific gamma interferon responses. These data highlight a central role for an acute but transient CD4 decrease, as well as CD4 + T-cell activation, as independent factors for prediction of set-point levels of virus replication. INTRODUCTIONHuman immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques are typically characterized by a slow, progressive loss of CD4 + T cells leading to immune incompetence and the onset of opportunistic infections (Fauci, 1988;Lifson et al., 1988). However, already by the early stages of infection, gut-homing CCR5-expressing CD4 memory subsets are being depleted (Brenchley et al., 2004;Li et al., 2005;Mattapallil et al., 2005Mattapallil et al., , 2004Veazey et al., 1998Veazey et al., , 2000 and CD4 + T-helper cell function is impaired (Clerici & Shearer, 1993; Koopman et al., 2001;Lane et al., 1985;McKay et al., 2003;Meyaard et al., 1996;Miedema et al., 1988;Shearer & Clerici, 1991). Recently, both events were found to be associated with the development of high virus load in SIVinfected macaques (Sun et al., 2007). Besides a possible direct immunosuppressive effect exerted by several HIV proteins (Cefai et al., 1992;Schindler et al., 2006;Westendorp et al., 1995), the formation of regulatory T cells, specifically the thymus-derived CD25 hi /FOXP3 + /CD152 + subset (Andersson et al., 2005;Estes et al., 2006;Hryniewicz et al., 2006;Kinter et al., 2004;Leng et al., 2002;Nilsson et al., 2006;Tsunemi et al., 2005), was found to be increased in HIV as well as in SIV infection, and was shown to contribute to suppression of HIV-specific immune responses (Kinter et al., 2004;Nilsson et al., 2006;Tsunemi et al., 2005).On the other hand, HIV infection induces a state of chronic immune activatio...

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Section: Zaundersmentioning

confidence: 99%

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

Koopman

Mortier

Hofman

et al. 2009

Journal of General Virology

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“…Consistently, CTLA-4Ig transgenic mice (blocking B7-CD28 interaction) infected with LCMV show no alternation of the function of virus specific cytotoxicity T lymphocytes (CTLs) [88]. In HIV infection, CTLA-4 expression is not altered on CD8 + T cells isolated from patients [89]. However, other reports suggest that CTLA-4 regulates CTL function during HBV or VSV infection.…”

Section: Different Role Of Pd-1 and Ctla-4 For Cd8 + T Cells Exhaustimentioning

confidence: 79%

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

Li¹,

Xu²,

Wang³

et al. 2013

J Clin Cell Immunol

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Emerging studies show that T cell exhaustion correlates well with increased expression levels of inhibitory receptors including Programmed cell death receptor 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) during chronic infections. Both inhibitory molecules play similar but non-redundant role in T cell exhaustion. Engagement of PD-1 and CTLA-4 by their ligands inhibits T cell proliferation, cytokine secretion, and attenuates immune responses. Blockade of PD-1 and CTLA-4 restores effector function of exhausted T cells. PD-1 and CTLA-4 could both recruit Src homology 2-containing tyrosine phosphatase 2 (SHP2) and inhibit activation of Akt. Nevertheless, PD-1 and CTLA-4 also target distinct signaling molecules to inhibit T cell function. In this review, we will discuss current understanding of PD-1 and CTLA-4 initiated signaling pathways, their regulatory roles in a variety of chronic viral infections, and their promising potential as targets to enhance T cell function for antiviral therapy.

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“…In the case of the probability binning algorithm used by FlowJo, bins are designed to contain equal numbers of cells (30). However, in the case of SOPHE, the empty bins contain information that is used to help define where clusters end, and also takes advantage of the tendency for populations to become more clearly defined as the number of parameters increases, based on our own experience with manual gating (9,13).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, inclusion of CD127 clearly reveals the full population of CD251 CD41 Tregs (13), which are even clearer if first divided using CD45RA/CD45RO. Furthermore, CD41 T cells that normally traffic through gutassociated lymphoid tissue, an important population that is particularly targeted by HIV-1 infection (14,15) express the combination of integrins alpha 4 (CD49d) and beta 7, and are most clearly visualized by first using CD45RA/CD45RO (9,10). However, as the number of parameters increases, the complexity of assigning lymphocytes to clusters of cells of similar phenotype greatly increases.…”

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Computationally efficient multidimensional analysis of complex flow cytometry data using second order polynomial histograms

et al. 2015

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Many methods have been described for automated clustering analysis of complex flow cytometry data, but so far the goal to efficiently estimate multivariate densities and their modes for a moderate number of dimensions and potentially millions of data points has not been attained. We have devised a novel approach to describing modes using second order polynomial histogram estimators (SOPHE). The method divides the data into multivariate bins and determines the shape of the data in each bin based on second order polynomials, which is an efficient computation. These calculations yield local maxima and allow joining of adjacent bins to identify clusters. The use of second order polynomials also optimally uses wide bins, such that in most cases each parameter (dimension) need only be divided into 4-8 bins, again reducing computational load. We have validated this method using defined mixtures of up to 17 fluorescent beads in 16 dimensions, correctly identifying all populations in data files of 100,000 beads in <10 s, on a standard laptop. The method also correctly clustered granulocytes, lymphocytes, including standard T, B, and NK cell subsets, and monocytes in 9-color stained peripheral blood, within seconds. SOPHE successfully clustered up to 36 subsets of memory CD4 T cells using differentiation and trafficking markers, in 14-color flow analysis, and up to 65 subpopulations of PBMC in 33-dimensional CyTOF data, showing its usefulness in discovery research. SOPHE has the potential to greatly increase efficiency of analysing complex mixtures of cells in higher dimensions. V C 2015 International Society for Advancement of Cytometry Key terms data analysis; clustering; high dimensions; complex data LYMPHOCYTES were originally viewed by light microscopy as small homogeneous round cells with minimal cytoplasm (1). Multiparameter flow cytometry, using currently available lasers, monoclonal antibodies and fluorochromes (2), has helped reveal the extremely complex heterogeneity of differentiated T and B cells with diverse immunological properties (3,4). It is possible to analyze 18 or more markers simultaneously on individual lymphocytes (2), and the development of additional labels will greatly increase this number. Study of 40 or more markers has already been achieved by the use of transition element isotopes as chelated antibody tags and mass cytometry, instead of fluorochromes (5,6).Addition of more parameters is an important goal of flow cytometric analysis of lymphocytes, because, paradoxically, instead of simply increasing complexity of the results, they can actually reveal important subsets with much greater clarity. This was originally best shown by the combination of 2 light scatter and 2 fluorescence parameters, CD45 and CD14, to clearly separate lymphocytes in blood from monocytes, granulocytes and red cell debris (7). In our experience, an important example is to first separate na€ ıve and memory T cells using CD45RA/CD45RO to measure expres-

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Infection of CD127⁺(Interleukin-7 Receptor⁺) CD4⁺Cells and Overexpression of CTLA-4 Are Linked to Loss of Antigen-Specific CD4 T Cells during Primary Human Immunodeficiency Virus Type 1 Infection

Cited by 78 publications

References 101 publications

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

Computationally efficient multidimensional analysis of complex flow cytometry data using second order polynomial histograms

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