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Updated: Dec 25, 2025
Author Spotlight: Achieving High-Purity In Vitro Differentiation of Th17 Cells Using Cytokine Concentration Modulation
Published on: October 25, 2024
CD28-Dependent CTLA-4 Expression Fine-Tunes the Activation of Human Th17 Cells
Scott M Krummey1, Christina R Hartigan2, Danya Liu2
1Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Insights
T helper 17 (Th17) cells, unlike Th1 cells, resist CD28 blockade, which paradoxically boosts Th17 responses. This highlights distinct CD28 and CTLA-4 pathway roles in T cell immunity and immunomodulation.
Area of Science:
- Immunology
- Cellular Biology
- T cell immunology
Background:
- T helper 17 (Th17) and T helper 1 (Th1) cells have differential responses to immune checkpoint blockade.
- CD28 and CTLA-4 are critical costimulatory and coinhibitory receptors on T cells, respectively.
- Understanding their distinct roles is crucial for targeted immunomodulation.
Purpose of the Study:
- To investigate the individual roles of CD28 and CTLA-4 costimulatory pathways in regulating Th1 versus Th17 cell responses.
- To elucidate the mechanisms underlying the differential sensitivity of Th1 and Th17 cells to CD28 blockade.
Main Methods:
- Utilized selective CD28 blockade with a domain antibody (dAb).
- Examined CD28 agonism effects on CTLA-4 expression.
- Investigated the role of the AKT signaling pathway in CTLA-4 regulation.
- Assessed the impact of FOXO1 and FOXO3 overexpression on CTLA-4 expression.
Main Results:
- Selective CD28 blockade inhibited Th1 cells but augmented Th17 responses.
- CD28 agonism led to significantly higher CTLA-4 expression on Th17 cells compared to Th1 cells.
- AKT inhibition more effectively reduced CTLA-4 expression on Th17 cells.
- FOXO1 and FOXO3 overexpression suppressed high CTLA-4 expression on Th17 cells, but not Th1 cells.
Conclusions:
- Th17 cells exhibit unique regulatory mechanisms involving CD28 and CTLA-4 signaling compared to Th1 cells.
- The heterogeneity within the CD4+ T cell compartment influences immunomodulatory strategies.
- These findings have implications for developing targeted therapies for immune-mediated diseases.
Abstract:
Previous work has demonstrated that Th17 memory cells but not Th1 cells are resistant to CD28/CTLA-4 blockade with CTLA-4 Ig, leading us to investigate the individual roles of the CD28 and CTLA-4 cosignaling pathways on Th1 versus Th17 cells. We found that selective CD28 blockade with a domain antibody (dAb) inhibited Th1 cells but surprisingly augmented Th17 responses. CD28 agonism resulted in a profound increase in CTLA-4 expression in Th17 cells as compared with Th1 cells. Consistent with these findings, inhibition of the CD28 signaling protein AKT revealed that CTLA-4 expression on Th17 cells was more significantly reduced by AKT inhibition relative to CTLA-4 expression on Th17 cells. Finally, we found that FOXO1 and FOXO3 overexpression restrained high expression of CTLA-4 on Th17 cells but not Th1 cells. This study demonstrates that the heterogeneity of the CD4+ T cell compartment has implications for the immunomodulation of pathologic T cell responses.
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