Control of T cell antigen reactivity via programmed TCR downregulation

Gallegos, Alena M.; Xiong, Huizhong; Leiner, Ingrid; Sušac, Bože; Glickman, Michael S.; Pamer, Eric G.; Heijst, Jeroen W. J. van

doi:10.1038/ni.3386

Cited by 77 publications

(97 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our finding of Tet 499 TCR downregulation associated with a strong antitumor effect is also in contrast to a report showing that TCR downregulation limits their efficacy of controlling microbial infection (48). We reason that this is likely due to the difference of antigen level and antigen stimulation duration between microbial infections and tumor lesion.…”

Section: Discussioncontrasting

confidence: 89%

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

Zhu

Peng

et al. 2017

Cancer Immunology Research

View full text Add to dashboard Cite

To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two α-fetoprotein–specific CD8+ T cells (Tet499 and Tet212) that had different antitumor effects. We found that Tet499 required high antigen doses for re-activation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet212 had a low threshold of re-activation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet499 cells expanded more than Tet212 upon re-encountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet212 and Tet499 cells correlated with their activation and differentiation states. Compared to Tet212, the population of Tet499 cells was less activated and contained more stem-like memory T cells (Tscm) that could undergo expansion in vivo. The TCR signaling strength on Tet499 was weaker than Tet212, correlating with more severe Tet499 TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet499 re-activation requires a high antigen dose. Weak TCR signaling of Tet499 cells in the effector stage will also protect them from exhaustion and apoptosis when they re-encounter persistent antigen in tumor lesion, which generates antitumor effects. Further investigation of TCR downregulation and manipulation of TCR signaling strength may help design cancer vaccines to elicit a mix of tumor-specific CD8+ T cells, including Tscm, capable of surviving antigen re-stimulation to generate antitumor effects.

show abstract

Section: Discussioncontrasting

confidence: 89%

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

Zhu

Peng

et al. 2017

Cancer Immunology Research

View full text Add to dashboard Cite

show abstract

“…Higher avidity TCRs may give the D b NP 366 and D b PA 224 ‐specific CD8 + T cells a proliferative advantage during clonal expansion and also make tetramer binding more efficient. A recent study of CD4 + T cells showed that T cells of intermediate avidity made the greatest contribution to pathogen clearance as they were less subjected to control of antigen reactivity via TCR downregulation 37. Similarly, the recall response of the higher avidity D b PA 224 ‐specific CD8 + T cells may be suppressed in an effort to circumvent excessive damage to the host.…”

Section: Discussionmentioning

confidence: 99%

Potential killers exposed: tracking endogenous influenza‐specific CD8⁺ T cells

et al. 2018

View full text Add to dashboard Cite

Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8+ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T‐cell priming events influence lasting memory, which is required for long‐term protection. However, the early responding, IAV‐specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T‐cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV‐specific CD8+ T‐cell population. Subsequently, IAV‐specific CD8+ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8+ T‐cell response. Importantly, the CD25+CD43+ phenotype identifies an inclusive population of early responding CD8+ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8+ T cells.

show abstract

“…of TF EPA (Association rule 4)No. of TF Promoter P -valueExperimental supportMonocytesIFN-gamma pathway51106.89 × 10 −4 [12]IL3-mediated signaling events46114.69 × 10 −3 [13]GMCSF-mediated signaling events43105.25 × 10 −3 [14]PDGF receptor signaling network4381.34 × 10 −2 [15]VEGF and VEGFR signaling network4492.10 × 10 −3 [16]CD4 + T cellIntegrin family cell surface interactions112132.59 × 10 −12 [17]IFN-gamma pathway107125.26 × 10 −12 [18]LKB1 signaling events107111.96 × 10 −12 [19]TCR signaling in naive CD4 + T cells103213.98 × 10 −8 [20]IL3-mediated signaling events10089.54 × 10 −13 [21]CD20 + B cellIntegrin family cell surface interactions6925.17 × 10 −11 [22]IL5-mediated signaling events6402.21 × 10 −11 [23]Insulin Pathway6303.15 × 10 −11 [24]mTOR signaling pathway6303.15 × 10 −11 [25]Sphingosine 1-phosphate (S1P) pathway6303.15 × 10 −11 [26]Immune cell-related functional annotations were enriched more in ‘promoter and extended regions for enhancer-promoter association (EPA)’ than promoters. Five annotations are shown in each cell type.…”

Section: Resultsmentioning

confidence: 99%

Characteristics of functional enrichment and gene expression level of human putative transcriptional target genes

Osato

2018

BMC Genomics

View full text Add to dashboard Cite

BackgroundTranscriptional target genes show functional enrichment of genes. However, how many and how significantly transcriptional target genes include functional enrichments are still unclear. To address these issues, I predicted human transcriptional target genes using open chromatin regions, ChIP-seq data and DNA binding sequences of transcription factors in databases, and examined functional enrichment and gene expression level of putative transcriptional target genes.ResultsGene Ontology annotations showed four times larger numbers of functional enrichments in putative transcriptional target genes than gene expression information alone, independent of transcriptional target genes. To compare the number of functional enrichments of putative transcriptional target genes between cells or search conditions, I normalized the number of functional enrichment by calculating its ratios in the total number of transcriptional target genes. With this analysis, native putative transcriptional target genes showed the largest normalized number of functional enrichments, compared with target genes including 5–60% of randomly selected genes. The normalized number of functional enrichments was changed according to the criteria of enhancer-promoter interactions such as distance from transcriptional start sites and orientation of CTCF-binding sites. Forward-reverse orientation of CTCF-binding sites showed significantly higher normalized number of functional enrichments than the other orientations. Journal papers showed that the top five frequent functional enrichments were related to the cellular functions in the three cell types. The median expression level of transcriptional target genes changed according to the criteria of enhancer-promoter assignments (i.e. interactions) and was correlated with the changes of the normalized number of functional enrichments of transcriptional target genes.ConclusionsHuman putative transcriptional target genes showed significant functional enrichments. Functional enrichments were related to the cellular functions. The normalized number of functional enrichments of human putative transcriptional target genes changed according to the criteria of enhancer-promoter assignments and correlated with the median expression level of the target genes. These analyses and characters of human putative transcriptional target genes would be useful to examine the criteria of enhancer-promoter assignments and to predict the novel mechanisms and factors such as DNA binding proteins and DNA sequences of enhancer-promoter interactions.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4339-5) contains supplementary material, which is available to authorized users.

show abstract

Control of T cell antigen reactivity via programmed TCR downregulation

Cited by 77 publications

References 50 publications

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

Potential killers exposed: tracking endogenous influenza‐specific CD8⁺ T cells

Characteristics of functional enrichment and gene expression level of human putative transcriptional target genes

Contact Info

Product

Resources

About

Control of T cell antigen reactivity via programmed TCR downregulation

Cited by 77 publications

References 50 publications

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

Potential killers exposed: tracking endogenous influenza‐specific CD8+ T cells

Characteristics of functional enrichment and gene expression level of human putative transcriptional target genes

Contact Info

Product

Resources

About

Potential killers exposed: tracking endogenous influenza‐specific CD8⁺ T cells