A Gene Expression Signature That Correlates with CD8+ T Cell Expansion in Acute EBV Infection

Greenough, Thomas C.; Straubhaar, Juerg R.; Kamga, Larisa; Weiss, Eric R.; Brody, Robin M.; McManus, Margaret; Lambrecht, Linda K.; Somasundaran, Mohan; Luzuriaga, Katherine

doi:10.4049/jimmunol.1401513

Cited by 21 publications

(25 citation statements)

References 73 publications

(144 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To minimize the amount of rare samples required, we assessed regulation of cell cycle and proliferation genes as a measure of proliferation following stimulation with anti-CD3/anti-CD28 mAbs (polyclonal stimulation), using RNA-seq transcript profiles as the readout. As shown in Figure 4A, mAb stimulation of DH cells triggered a transcriptional response that included genes implicated in in vivo activation of CD8 T cells (28). When compared with DL cells (Figure 4B), DH cells responded to polyclonal stimulation by upregulation of inhibitory receptors, and down regulation of multiple cell cycle genes.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

Long¹,

Thorpe²,

DeBerg³

et al. 2016

Sci. Immunol.

178

177

View full text Add to dashboard Cite

Biologic treatment of T1D typically results in transient stabilization of C-peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. Here, we used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in subjects with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1. These cells expanded after treatment, with levels peaking after 3–6 months. To functionally characterize these exhausted-like T cells, we isolated memory CD8 TIGIT+KLRG1+ T cells from responders and showed that they exhibited expanded TCR clonotypes, indicative of prior in vivo expansion; recognized a broad-based spectrum expressed of environmental and auto-antigens; and were hypo-proliferative during polyclonal stimulation, increasing expression of IR genes and decreasing cell cycle genes. Triggering these cells with a recombinant ligand for TIGIT during polyclonal stimulation further downregulated their activation, demonstrating their exhausted phenotype was not terminal. These findings identify and functionally characterize a partially exhausted cell type associated with response to teplizumab therapy and suggest that pathways regulating T cell exhaustion may play a role in successful immune interventions for T1D.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Blue dots, selected CD8 T cell genes that correlate with T cell expansion in acute EBV infection (28); grey dots, all other genes Horizontal dashed line, FDR = 0.05; vertical, dashed line, log(fold-change) = 0. (B) Differential gene expression in CD3/anti-CD28 mAb stimulated DH versus DL cells.…”

Section: Figurementioning

confidence: 99%

Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

Long¹,

Thorpe²,

DeBerg³

et al. 2016

Sci. Immunol.

178

177

View full text Add to dashboard Cite

show abstract

“…B cells were isolated from whole blood using a RosetteSep human B-cell kit (Stemcell Technologies, Vancouver, BC, Canada). DNA was extracted using a Qiagen DNeasy blood and tissue kit (Valencia, CA), and blood viral loads were measured using a Roche LightCycler EBV quantification kit (Roche, Indianapolis, IN) (17,46).…”

Section: Methodsmentioning

confidence: 99%

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

Self Cite

View full text Add to dashboard Cite

The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM.IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro. The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

show abstract

“…20% develop clinical mononucleosis upon primary infection. Virus‐specific ASTC play a crucial role during acute EBV infection, when EBV‐specific ASTC can comprise up to 10% of circulating CTL, but the presence of EBV‐specific ASTC is also important for lifelong control of EBV‐related disease …”

Section: Discussionmentioning

confidence: 99%

“…The epitope ELAGIGILTV is an analogue to the peptide Melan-A/MART-1 encoded by the gene MLANA, which is expressed in normal melanocytes as well as in most melanoma samples and cell lines. As the naturally occurring Melan-A [26][27][28][29][30][31][32][33][34][35] (EAAGIGILTV) peptide binds poorly to HLA A*0201, Valmori et al developed the analogue ELAGIGILTV by a single-amino acid substitution, 22 yielding stronger HLA A*0201 binding as well as a more efficient recognition by tumour-reactive T cells and melanoma-reactive cell lines. In addition to detection of ELAGIGILTV-reactive T cells in patients with melanoma, ELAGIGILTV-reactive CTL have also been described in many healthy donors, often exhibiting a memory phenotype.…”

Section: Discussionmentioning

confidence: 99%

Development of an epitope panel for consistent identification of antigen‐specific T‐cells in humans

Fløe

Løppke²,

Hilberg

et al. 2017

Immunology

View full text Add to dashboard Cite

We aimed to establish a panel of MHC-peptide multimers suitable as a positive control in the detection of HLA A*0201 restricted antigen specific T cells (ASTC) by flow cytometry. MHC Dextramers were loaded with HLA A*0201 binding peptides from viral antigens and melanoma targets identified from a literature search and in silico prediction. Peripheral blood mononuclear cells (PBMC) from healthy donors were analysed with the MHC Dextramers using flow cytometry. The best performing epitopes were tested on PBMC from patients undergoing testing for Mycobacterium tuberculosis infection to assess the coverage of this epitope panel. Of 21 candidate epitopes, ASTC could be detected against 12 (57·1%) in at least one of 18 healthy blood donors. Reactivity to two or more epitopes was seen in 17 of the 18 donors (94·4%). We selected the six best-performing epitopes and demonstrated a positive response in 42 (97·7%) of 43 patient samples (healthy, latent and active M. tuberculosis infection). The selected panel of six antigenic epitopes sufficed as a positive control in the detection of ASTC in HLA A*0201. Performance was robust in different stages of latent and active M. tuberculosis infection, indicating reliability also during infection.

show abstract

A Gene Expression Signature That Correlates with CD8+ T Cell Expansion in Acute EBV Infection

Cited by 21 publications

References 73 publications

Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Development of an epitope panel for consistent identification of antigen‐specific T‐cells in humans

Contact Info

Product

Resources

About