CD28 Costimulation and Downstream Pathways

What downstream signaling pathways are altered when CD28 costimulation is blocked?

CD28 costimulation blockade disrupts proximal TCR signaling, suppresses transcription factors, reduces IL-27 pathway signaling, impairs metabolic pathways, and when selective, upregulates regulatory pathways.

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, which cascades to strongly 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 in both monocytes and CD4+ T cells. Metabolically, CD28 blockade disrupts the AKT-mTOR-HIF-1α axis, reducing glucose transporter Glut1 expression and glycolytic enzyme levels.

Selective CD28 blockade while preserving CTLA-4 promotes regulatory pathways, upregulating Foxp3, PD-1, IDO, and CTLA-4 expression, contributing to tolerance induction. Alternative costimulatory pathways can sustain T cell responses when CD28 is eliminated.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects relevant to the research question.

Criteria for Screening Sources:

• CD28 Blockade Intervention: Investigation of CD28 costimulation blockade.
• Signaling Pathway Measurement: Measurement of downstream signaling pathways post-blockade.
• Appropriate Controls: Inclusion of appropriate control groups.
• Experimental Study Type: In vitro, ex vivo, or in vivo studies.
• Mechanistic Focus: Inclusion of mechanistic signaling pathway data.
• Blockade vs Stimulation: Examination of CD28 blockade.
• Publication Type: Full research articles only.
• Pathway Analysis Inclusion: Inclusion of signaling pathway analysis.

Data Extraction Categories:

• CD28 Blockade Method: Extract details about blockade methods.
• Experimental System: Model system, context, species, etc.
• Target Cell Types: Specific cell types studied.
• Signaling Pathways Analyzed: Pathways that were measured.
• Pathway Changes Observed: Specific alterations in pathways due to blockade.
• Mechanistic Insights: Explanations for pathway changes due to blockade.
• Functional Consequences: Functional outcomes from altered pathways.

Results

Characteristics of Included Studies

Ten studies focused on downstream signaling pathway alterations post-CD28 costimulation blockade. Most utilized murine systems, with a few involving human cells.

Proximal TCR Signaling Pathways

CD28 blockade impaired early TCR signaling events, diminished tyrosine phosphorylation of crucial pathways, including Ca2+/calcineurin, ERK/MAPK, and JNK.

Transcription Factor Activation

CD28 blockade inhibited transcription factors such as NF-κB and AP-1.

IL-27 Signaling Pathway

Insights established IL-27 signaling as a target affected by CD28 blockage, including reduced expression of key components related to proliferation and differentiation.

Metabolic Signaling Pathways

Impairments in metabolic fitness due to CD28 blockade involved reduced glucose transporter expression and decreased mitochondrial function.

Regulatory and Tolerance-Associated Pathways

CD28 blockade facilitated the promotion of immune regulatory pathways, enhancing tolerance mechanisms post-transplantation.

Alternative Costimulatory Pathways

Identification of compensatory pathways indicates an ability to sustain T cell responses under CD28 blockade.

Functional Consequences Across Studies

The blockade resulted in a consistent suppression of T cell proliferation and cytotoxic responses across different models, ultimately leading to prolonged allograft survival and tolerance induction.