Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice
Open accessAbstract
Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis.
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Removing Treg cells immediately before CD28SA treatment in mice produced measurable blood TNF, IL-2, and IL-6, but no visible distress.
“when we removed Treg cells immediately before applying the CD28SA to mice, considerable amounts of circulating TNF, IL-2, and IL-6 became detectable [15], although this did not result in visible distress.”
From The rise and fall of the <scp>CD</scp> 28 superagonist <scp>TGN</scp> 1412 and its return as <scp>TAB</scp> 08: a personal account (2016) · cites this paper as [15]
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“We also investigated the levels of other circulating cytokines (ILs 4, 5, 6, 10, 12; IFNc and TNF) which had contributed to the syndrome observed in the human volunteers of the TGN1412 study [20].”
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- Authors
- Gogishvili, T., Langenhorst, D., Lühder, F., Elias, F., Elflein, K., Dennehy, K. M., Gold, R., & Hünig, T.
- Affiliations
- University of Würzburg (DE)
- Hertie Foundation (DE)
- St. Josef-Hospital (DE)
- Corresponding author
- Hünig, Thomas
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-02-27
- Volume
- 4
- Issue
- 2
- Pages
- e4643
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2645706
- OpenAlex
- W2068582444
- Cited by
- 79
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 8 · 2013: 5 · 2012: 11
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- GRO (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- regulatory T cells, TGN1412, cytokine release syndrome, Treg activation, corticosteroid prophylaxis, dexamethasone, inflammatory cytokines, Treg depletion
- MeSH terms
- Adrenal Cortex Hormones, Animals, Antibodies, Monoclonal, Lymphocyte Activation, Cytokines, CD28 Antigens, Cell Proliferation, T-Lymphocytes, Regulatory, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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