Dysfunctional HIV-Specific CD8+ T Cell Proliferation Is Associated with Increased Caspase-8 Activity and Mediated by Necroptosis

Gaiha, Gaurav D.; McKim, Kevin J.; Woods, Matthew; Pertel, Thomas; Rohrbach, Janine; Barteneva, Natasha S.; Chin, Christopher R.; Liu, Dongfang; Soghoian, Damien Z.; Cesa, Kevin; Wilton, Shannon; Waring, Michael T.; Chicoine, Adam; Doering, Travis A.; Wherry, E. John; Kaufmann, Daniel E.; Lichterfeld, Mathias; Brass, Abraham L.; Walker, Bruce D.

doi:10.1016/j.immuni.2014.12.011

Cited by 65 publications

(58 citation statements)

References 68 publications

(91 reference statements)

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“…Moreover, one of the driving modules behind this signature was also strongly enriched for genes identified in HIV-specific CD8 + T cells from patients that maintain long-term control of viral replication (Gaiha et al, 2014), lending further support to this notion.…”

Section: Discussionmentioning

confidence: 71%

“…c5 was also enriched for a signature associated with long-term viral control in HIV (Gaiha et al, 2014) and correlated with CD4 help status as measured by our targeted CD4 assays. While not comprehensively assessing all targeted CD4 epitopes in a patient, this assay captures the decline of HCV-specific CD4 + T cell populations in chronic infection (Schulze zur Wiesch et al, 2012).…”

Section: Resultsmentioning

confidence: 93%

“…subject sex and age, HCV viral load, alanine transaminase levels (ALT), and time from infection, as well as presence of HCV-specific CD4 + T cells targeting a set of dominant viral epitopes (Figure 5A, STAR Methods). To further link modules to biological function we tested them for enrichment of: 1) differential expression signatures of CD8 + T cells in different disease models (HCV (from Figure 2), HIV (Gaiha et al, 2014), LCMV (Doering et al, 2012), and cancer (Singer et al, 2016)) or T cell memory states (Subramanian et al, 2005), 2) module gene signatures of antigen-specific CD8 + T cells in chronic vs acute LCMV infection (Doering et al, 2012), and 3) functional gene sets related to immune pathways (Langfelder and Horvath, 2008), gene ontology, and KEGG pathway databases (Ashburner et al, 2000; Kanehisa, 2000) (Figures 5B, 5C, and 5D, Tables S3 and S7, STAR Methods).…”

Section: Resultsmentioning

confidence: 99%

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Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection

et al. 2017

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Summary Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection but these are not well-studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that were linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.

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Section: Discussionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection

et al. 2017

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“…Along similar lines, diverse bacterial pathogens including Serratia marcescens , Staphylococcus aureus , Streptococcus pneumoniae , L. monocytogenes , and uropathogenic Escherichia coli produce pore-forming toxins that trigger Ripk1 -, Ripk3 -, and Mlkl -dependent necroptosis in macrophages, which mechanistically contributes to bacterial hemorrhagic pneumonia (136). Engagement of the T cell receptor in HIV-1-specific CD8 + CTLs from patients with chronic HIV-1 infection (but not from patients who spontaneously control viremia) fails to promote normal proliferation, which has been attributed to the activation of RIPK3 and consequent necroptosis (137). Moreover, Nec-1 limits the formation of syncytia between HIV-1 + CD4 + T cells (138), which suggests that RIPK1 plays a pathogenic role in this setting.…”

Section: Pathophysiological Relevance Of Necroptosismentioning

confidence: 99%

Necroptosis: Mechanisms and Relevance to Disease

Galluzzi

Kepp

Chan

2017

Annu. Rev. Pathol. Mech. Dis.

505

398

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Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion. Moreover, human tumors appear to obtain an advantage from the downregulation of key components of the molecular machinery for necroptosis. Although such an advantage may stem from an increased resistance to adverse microenvironmental conditions, accumulating evidence indicates that necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance. Here, we discuss the molecular mechanisms and relevance to disease of necroptosis.

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“…2). A growing list of such candidates have been described (29,(31)(32)(33)(34)(35)(36)(37). For example, partial inhibition of Blimp-1 in exhausted T cells led to the downregulation of multiple inhibitory receptors and prevented exhaustion (29).…”

Section: Improving On Pd-1 Blockade and Immune Modulationmentioning

confidence: 99%

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

Gilboa

Berezhnoy

Schrand

2015

Cancer Immunology Research

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Modulating the function of immune receptors with antibodies is ushering in a new era in cancer immunotherapy. With the notable exception of PD-1 blockade used as monotherapy, immune modulation can be associated with significant toxicities that are expected to escalate with the development of increasingly potent immune therapies. A general way to reduce toxicity is to target immune potentiating drugs to the tumor or immune cells of the patient. This Crossroads article discusses a new class of nucleic acid-based immune-modulatory drugs that are targeted to the tumor or to the immune system by conjugation to oligonucleotide aptamer ligands. Cell-free chemically synthesized short oligonucleotide aptamers represent a novel and emerging platform technology for generating ligands with desired specificity that offer exceptional versatility and feasibility in terms of development, manufacture, and conjugation to an oligonucleotide cargo. In proof-of-concept studies, aptamer ligands were used to target immune-modulatory siRNAs or aptamers to induce neoantigens in the tumor cells, limit costimulation to the tumor lesion, or enhance the persistence of vaccine-induced immunity. Using increasingly relevant murine models, the aptamer-targeted immune-modulatory drugs engendered protective antitumor immunity that was superior to that of current "gold-standard" therapies in terms of efficacy and lack of toxicity or reduced toxicity. To overcome immune exhaustion aptamer-targeted siRNA conjugates could be used to downregulate intracellular mediators of exhaustion that integrate signals from multiple inhibitory receptors. Recent advances in aptamer development and second-generation aptamer-drug conjugates suggest that we have only scratched the surface.

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Dysfunctional HIV-Specific CD8+ T Cell Proliferation Is Associated with Increased Caspase-8 Activity and Mediated by Necroptosis

Cited by 65 publications

References 68 publications

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection

Necroptosis: Mechanisms and Relevance to Disease

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

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