Elicit: CD28 Costimulation and Downstream Pathways
CD28 Costimulation and Downstream Pathways
What downstream signaling pathways are altered when CD28 costimulation is blocked?
CD28 costimulation blockade disrupts proximal TCR signaling (ζ chain, ZAP-70, Ca2+/calcineurin, ERK/MAPK, JNK), suppresses transcription factors (NF-κB, AP-1), reduces IL-27 pathway signaling (STAT3, pSTAT1), impairs metabolic pathways (AKT-mTOR-HIF-1α axis, glucose uptake, glycolysis), and when selective, upregulates regulatory pathways (Foxp3, PD-1, IDO, CTLA-4).
Abstract
CD28 costimulation blockade disrupts multiple downstream signaling pathways across a coordinated cascade. At the proximal level, CD28 blockade impairs TCR-induced tyrosine phosphorylation of the ζ chain and ZAP-70, leading to diminished Ca2+/calcineurin, ERK/MAPK, and JNK pathway activation. Transcription factors critical for T cell activation, particularly NF-κB and AP-1, are potently suppressed. CD28:B7 signaling is required for monocyte IL-27 production, and blockade decreases IL-27 pathway components (p28, EBI3, IL-27R, STAT3, pSTAT1) in both monocytes and CD4+ T cells. Metabolically, CD28 blockade disrupts the AKT-mTOR-HIF-1α axis, reducing glucose transporter Glut1 expression, glycolytic enzyme levels, and mitochondrial oxygen consumption.
Methods
We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question.
Records from Elicit search
- n = 200
- Papers screened using: CD28 Blockade Intervention, Signaling Pathway Measurement, Appropriate Controls, Experimental Study Type, Mechanistic Focus, Blockade vs Stimulation, Publication Type, Pathway Analysis Inclusion
- n = 200 Papers screened out
- n = 190 Papers included for extraction
Data extraction
CD28 Blockade Method
- Specific agent used: Anti-CD28 antibody
- Dosage/concentration: 1 µg/ml
- Timing of blockade: Not specified
- Route of administration: Not specified
Experimental System
- Model system: In vitro cell culture, animal model
- Disease context: Transplantation, autoimmunity
- Species: Human, mouse
Target Cell Types
- Primary cell type studied: CD4+ T cells
- Cell activation state: Activated
Signaling Pathways Analyzed
- Pathway names: NF-κB, AKT, mTOR
Pathway Changes Observed
- Direction of change: Downregulated
- Magnitude of effect: 30-50% reduction in glycolytic enzymes
Mechanistic Insights
- Proposed mechanism: CD28 blockade disrupts T-cell metabolic fitness by reducing glucose utilization.
Functional Consequences
- T cell proliferation: Suppressed
- Cytokine production: Altered
- Therapeutic implications: Novel therapeutic opportunities for disease-modifying strategies.
Results
Characteristics of Included Studies
Ten studies examining downstream signaling pathway alterations following CD28 costimulation blockade.
Study Details
| Study | Full text retrieved? | Model system | Disease context | Species | CD28 blockade method | Target cell types |
|---|---|---|---|---|---|---|
| G. Gorgun et al., 2007 | No | Ex vivo MLR | Transplantation | Human | Anti-B7.1/B7.2 mAbs, 72h | CD4+ T cells, monocytes |
| Koji Kishimoto et al., 2000 | Yes | Cardiac transplant | Transplantation | Mouse | CTLA4Ig 250 µg ip, d2 | T cells (Th1/Th2) |
| G. Gorgun et al., 2008 | No | Ex vivo MLR | Transplantation | Human | Anti-B7.1/B7.2 mAbs, 72h | CD4+ T cells, monocytes |
| A. Habicht et al., 2007 | No | Skin transplant | Transplantation | Mouse | CD28 knockout | CD4+ and CD8+ effector-memory T cells |
| Hui Zhang et al., 2019 | Yes | Human artery-NSG chimera | Vasculitis (GCA) | Human/Mouse | Anti-CD28dAb | CD4+ T cells, CD4+CD103+ TRM |
| C. Olsson et al., 1999 | No | In vitro blastoid T cells | Normal activation | Mouse | CTLA-4 mAb | CD4+/CTLA-4+ T cells |
| J. Woodward et al., 1996 | No | Cardiac transplant | Transplantation | Mouse | CTLA4Ig + anti-CD2 mAb | T lymphocytes (CD4+, CD8+) |
| David V. Mathews et al., 2018 | No | Transplant | Transplantation | Mouse | Belatacept | CD8+ memory T cells |
| L. Tuosto & O. Acuto, 1998 | No | In vitro T cells | Normal activation | Human (Jurkat), Mouse | CD28/B7 blockade | Jurkat T cells, primary T cells |
| T. Zhang et al., 2011 | Yes | Cardiac transplant | Transplantation | Mouse | α28scFv 100 µg bid | CD4+ T cells, regulatory T cells |
Synthesis
The studies reveal a coordinated cascade of signaling disruptions initiated by CD28 blockade. The discovery that CD28:B7 signaling is required for monocyte IL-27 production reveals indirect effects on bystander cells beyond the directly targeted T cells. Metabolic effects occur rapidly, affecting T cell proliferation and differentiation.
References
[1]: (G. Gorgun et al. 2007) Costimulatory Blockade during Mixed Lymphocyte Reaction Prevents IL-27 Upregulation and Signaling. Blood [2]: (Koji Kishimoto et al. 2000) The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo. Journal of Clinical Investigation [3]: (Hui Zhang et al. 2019) CD28 Signaling Controls Metabolic Fitness of Pathogenic T Cells in Medium and Large Vessel Vasculitis. Journal of the American College of Cardiology