Details for: CL0000920

Cell ID: CL0000920

Cell Name: CD8-positive, CD28-negative, alpha-beta regulatory T cell

Description: CD8-positive, alpha-beta positive regulatory T cell with the phenotype CD28-negative and FoxP3-positive.

Synonyms: CD8+CD28- T cell, CD8+CD28- T lymphocyte, CD8+CD28- T(reg), CD8+CD28- T-cell, CD8+CD28- T-lymphocyte, CD8+CD28- Treg, CD8-positive, CD28-negative T(reg), CD8-positive, CD28-negative Treg, CD8-positive, CD28-negative, alpha-beta regulatory T lymphocyte, CD8-positive, CD28-negative, alpha-beta regulatory T-cell, CD8-positive, CD28-negative, alpha-beta regulatory T-lymphocyte

Selected Context(s): Overall

Gene Significance Landscape

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Genes

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Cell Significance Index (CSI) is uniquely calculated to reveal cell-specific gene markers. More info here

Significant Genes List

Genes with the highest and lowest Percentile Rank Scores (PRS) for CD8-positive, CD28-negative, alpha-beta regulatory T cell within the selected context(s).

Gene ID: A unique numerical identifier for this specific gene.
Symbol: Shortened abbreviation or name that represents this gene.
Ensembl Gene ID: A unique identifier assigned by Ensembl for genomic data mapping.
CSI Score: A combined effect size and statistical significance measure for CD8-positive, CD28-negative, alpha-beta regulatory T cell. Higher scores indicate a stronger, more significant difference in expression.
(Previously described as "Fold Change", but now represents Cliff's Delta × –log10(p).)

Gene ID: A unique numerical identifier for this specific gene.
Symbol: Shortened abbreviation or name that represents this gene.
Ensembl Gene ID: A unique identifier assigned by Ensembl for genomic data mapping.
CSI Score: A combined effect size and statistical significance measure for CD8-positive, CD28-negative, alpha-beta regulatory T cell. Higher scores indicate a stronger, more significant difference in expression.
Average CSI: csi sum / gene count
Cell network configuration

This network visualizes key genes for CD8-positive, CD28-negative, alpha-beta regulatory T cell. It primarily includes:
1. Top genes highly significant for this cell (Num. Top Cell Genes - based on the 'Min. CSI' setting).
2. Any additional specific 'Context Genes' you add below.
The final network is a combined view. Choose an Interaction Source (pathways or protein interactions) and optionally compare CSI scores with a Baseline Cell Type.

Maximum number of selected genes.
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Select a context for the target cell.
Target Cell for CSI:  CD8-positive, CD28-negative, alpha-beta regulatory T cell (CL0000920)

 Legend
Nodes (Genes):
 Query Gene
Node size also reflects Target Cell CSI magnitude.
Node Color (Target Cell CSI in specific network):
 Very High
 High
 Medium
 Low
 Very Low
 N/A or Not Sig.
Edges (Interactions):
 STRING (Protein-Protein)
 ONTOLOGY (Shared Pathway)
 Colors vary by pathway category; default arrow applies.

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## Summary The [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) is a distinct subset of regulatory T lymphocytes characterized by the expression of the CD8 coreceptor, an alpha-beta T-cell receptor, and the transcription factor FoxP3, but which notably lacks the costimulatory molecule CD28. **Overall**, the gene significance profile suggests that the defining feature of this cell type is not the expression of unique immunological effector molecules, but rather a state of exceptionally high and specific metabolic and biosynthetic activity. The top markers for this cell are dominated by genes involved in core cellular processes, including glycolysis ([GAPDH](/details-gene/2597)), protein turnover ([UBC](/details-gene/7316), [SUMO2](/details-gene/6613)), and mitochondrial respiration ([COX1](/details-gene/4512), [ATP6](/details-gene/4508)), indicating a cell that is metabolically poised for sustained function. ## Key Characteristics and Function Analysis of the top marker genes reveals a cell state optimized for high metabolic throughput, robust protein homeostasis, and specialized intercellular signaling. * **Metabolic and Biosynthetic Hub:** A striking number of top markers are involved in fundamental energy metabolism and biosynthesis. High specificity for glycolytic enzymes like [GAPDH](/details-gene/2597) and multiple components of the mitochondrial electron transport chain, such as [COX1](/details-gene/4512), [ATP6](/details-gene/4508), and [ND3](/details-gene/4537), suggests that these cells have a high energy demand supported by both glycolysis and oxidative phosphorylation. This metabolic state is further supported by the prominence of genes essential for protein synthesis, folding, and degradation, including ubiquitin pathway components ([UBC](/details-gene/7316), [UBE2D3](/details-gene/7323), [SKP1](/details-gene/6500)), RNA binding proteins ([HNRNPA2B1](/details-gene/3181), [PABPC1](/details-gene/26986)), and the SUMO E2 conjugating enzyme ([SUMO2](/details-gene/6613)). This implies a high rate of protein turnover, potentially to maintain effector functions or withstand cellular stress. * **Specialized Regulatory and Signaling Machinery:** Beyond metabolic programming, several key markers point to specific functional roles. The high significance of [HLA E](/details-gene/3133), a non-classical MHC class I molecule, suggests a primary regulatory mechanism involving the inhibition of natural killer (NK) cells or other T cells through interaction with the CD94/NKG2A receptor. Furthermore, the endoplasmic reticulum protein [SARAF](/details-gene/51669), a negative regulator of store-operated calcium entry ([Link](https://doi.org/10.1016/j.cell.2012.01.055)), may be crucial for fine-tuning the cellular response to T-cell receptor stimulation, possibly maintaining the cell in a controlled, non-exhausted state of activation consistent with a regulatory role. The presence of 14-3-3 signaling adaptors ([YWHAB](/details-gene/7529), [YWHAZ](/details-gene/7534)) further underscores the cell's active and tightly regulated signaling network. * **Control of Cell Fate:** The significant expression of the anti-proliferative gene [BTG1](/details-gene/694) is consistent with the profile of a terminally differentiated cell that has limited capacity for clonal expansion, a characteristic feature of certain regulatory and memory T cell populations. * **Lineage and Functional Definition by Exclusion:** The anti-marker profile helps to refine the cell's identity. The low significance for the T-cell receptor gamma constant gene [TRGC2](/details-gene/6967) confirms its alpha-beta T cell lineage. Similarly, the lack of significance for the potent activating receptor [KLRK1](/details-gene/22914) (NKG2D) and the costimulatory ligand [CD70](/details-gene/970) aligns with a suppressive or regulatory function rather than a primary cytotoxic role. ## Clinical Significance and Contextual Roles While this analysis is based on an **Overall** context, the unique characteristics of the [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) have important clinical implications. Cells with a CD8+CD28- phenotype are known to accumulate during chronic viral infections and with age, contributing to the landscape of immunosenescence. Their regulatory capacity, however, suggests they may play a dual role in disease. The cell's highly metabolic nature could render it either highly resilient or particularly vulnerable within metabolically challenging microenvironments, such as tumors or sites of chronic inflammation. The high expression of antioxidant enzymes like [SOD1](/details-gene/6647) suggests a robust adaptation to handle oxidative stress, a key survival advantage in inflammatory settings. The potential regulatory mechanism mediated by [HLA E](/details-gene/3133) is of significant clinical interest, as modulating the activity of NK cells and other cytotoxic lymphocytes is a central goal in cancer immunotherapy and transplantation. ## Potential Mechanisms and Research Directions 1. **Hypothesis:** The defining characteristic of the [CD8-positive, CD28-negative, alpha-beta regulatory T cell](/details-cell/CL0000920) is not lineage-defining surface markers, but a hard-wired metabolic program of "sustained readiness." The uniquely high expression of core metabolic and protein-turnover machinery allows the cell to exert immediate and continuous regulatory functions without undergoing significant proliferation, distinguishing it from conventional T cells that must ramp up metabolism upon activation. * **Surprising Findings:** The near-total absence of classic immune effector or T-cell lineage genes among the top markers is unexpected. Instead, the profile is dominated by ubiquitous housekeeping genes, suggesting that for this cell, identity is defined by its physiological state and metabolic capacity rather than by a unique molecular toolkit. * **Testable Questions:** How does acute inhibition of glycolysis (e.g., with 2-DG) or oxidative phosphorylation (e.g., with oligomycin) specifically impact the in vitro suppressive capacity of these cells compared to conventional CD8+ T cells or CD4+ regulatory T cells? 2. **Hypothesis:** The primary suppressive function of this cell population is mediated through direct, contact-dependent inhibition of NK cells and activated CD8+ T cells via the non-classical MHC molecule [HLA E](/details-gene/3133). This pathway represents a dominant, non-redundant mechanism of action for this specific regulatory subset. * **Surprising Findings:** While regulatory T cells are often studied for their cytokine secretion or metabolic competition, the data strongly highlights [HLA E](/details-gene/3133), a molecule primarily known for its role in innate immune modulation, as a top defining marker. This points to a regulatory mechanism that bridges the adaptive and innate immune systems. * **Testable Questions:** In a co-culture system, does a blocking antibody against [HLA E](/details-gene/3133) or its receptor, NKG2A, restore the cytotoxic function of NK cells or effector T cells that have been suppressed by [CD8-positive, CD28-negative, alpha-beta regulatory T cells](/details-cell/CL0000920)?