Mitogenic CD28 signals require the exchange factor Vav1 to enhance TCR signaling at the SLP-76-Vav-Itk signalosome.
Open accessAbstract
Almost all physiological T cell responses require costimulation—engagement of the clonotypic TCR with MHC/Ag and CD28 by its ligands CD80/86. Whether CD28 provides signals that are qualitatively unique or quantitatively amplify TCR signaling is poorly understood. In this study, we use superagonistic CD28 Abs, which induce T cell proliferation without TCR coligation, to determine how CD28 contributes to mitogenic responses. We show that mitogenic CD28 signals require but do not activate the proximal TCR components TCRζ and Zap-70 kinase. In cell lines lacking proximal TCR signaling, an early defect in the CD28 pathway is in phosphorylation of the adaptor molecule SLP-76, which we show is essential for recruitment of the exchange factor Vav leading to Ca2+ flux and IL-2 production. Point mutations in CD28 that result in diminished Vav phosphorylation also result in defective Ca2+ flux, IL-2 production, and Tec-kinase phosphorylation. Using Vav1-deficient mice, we further demonstrate the importance of Vav1 for efficient proliferation, IL-2 production, and Ca2+ flux. Our results indicate that CD28 signals feed into the TCR signaling pathway at the level of the SLP-76 signalosome.
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Expression of a functional TCR and activation of Src-kinases are required for ANC28.1-mediated calcium flux, whereas activation of PI3K appears dispensable.
“Hence, similar to the situation in rat T cells [11], [12] expression of a functional TCR and the activation of Src-kinases are required for ANC28.1-mediated calcium flux, whereas activation of PI3K appears to be dispensable.”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [12]
The Results (p. 4) support a requirement for an intact TCR/CD3 complex in superagonistic CD28 signaling, and the Results (p. 6) link that signaling to calcium flux. The Discussion (p. 8) suggests PI3K/PKB is not of major importance, but does not establish that PI3K activation is dispensable for calcium flux. Our copy does not show that Src-kinase activation is required or identify ANC28.1 as the antibody tested. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe latter assumption was based on the observation that anti-rat CD28 superagonists do not induce phosphorylation of AKT and that mutation of the PI3K binding site within the cytoplasmic domain of CD28 did not ablate CD28SA-mediated IL-2 production.
“The latter assumption was based on the observation that anti-rat CD28 superagonists do not induce phosphorylation of AKT and that mutation of the PI3K binding site within the cytoplasmic domain of CD28 did not ablate CD28SA-mediated IL-2 production [12].”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [12]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA recent report suggested that IL-2 production upon CD28SA-stimulation of rat T cells is primarily mediated via the SLP76/Vav-module and does not require activation of PI3K.
“A recent report suggested that IL-2 production upon CD28SA-stimulation of rat T cells is primarily mediated via the SLP76/Vav-module and does not require activation of PI3K [12].”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [12]
The Discussion (p. 8) links the SLP-76–Vav–Itk signalosome to IL-2 production, but the direct SLP-76 and Vav evidence comes from cell lines and transgenic mice, not primary rat T cells. In primary rat T cells, the Results (p. 5) find weak PKB phosphorylation and suggest the PI3K/PKB pathway is not a major contributor; the paper does not establish that PI3K activation is unnecessary. (LLM, conf=0.88)
Experimental — accuracy not yet measuredANC28.1 stimulation did not result in detectable tyrosine phosphorylation of ZAP70 in human T cells.
“In agreement with data obtained in rat T cells [12], ANC28.1 stimulation did not result in a detectable tyrosine phosphorylation of the protein tyrosine kinase ZAP70 (Fig. 1B, middle panel) although ZAP70 is believed to be primarily responsible for LAT phosphorylation upon TCR-stimulation.”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [12]
The Results (p. 4) report that CD28-superagonist stimulation did not induce Zap-70 phosphorylation in human Jurkat T cells. The paper does not identify the antibody as ANC28.1 in the passages examined, so it supports the finding but not the claim about that specific antibody. (LLM, conf=0.82)
Experimental — accuracy not yet measuredANC28.1-induced Ca++ signal required expression of a functional TCR.
“(i) we show that (similar to rat T cells [12]) the Ca++-signal produced by ANC28.1 required expression of a functional TCR (Fig. 2B);”
From Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies (2008) · cites this paper as [12]
CD28 superagonist-triggered T-cell responses do not require overt T-cell receptor engagement, but T-cell receptor presence is needed to generate basal downstream substrate at the slp76 signalosome for CD28-mediated signal amplification.
“although no overt engagement of the TCR is required to obtain CD28SA-triggered T-cell responses, its presence is needed to generate a basal level of downstream substrate at the slp76 signalosome for signal amplification by CD28 [13].”
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 [13]
The inability of T cells in freshly isolated peripheral blood mononuclear cells to respond to soluble CD28 superagonist results from the dependence of CD28 signal transduction on at least a weak T-cell receptor signal, which is then amplified by CD28-derived signals at the slp76 signalosome.
“the inability of the T cells contained in freshly isolated PBMCs to respond to soluble CD28SA is the consequence of the dependence of CD28 signal transduction on at least a weak signal from the TCR, which is then amplified by CD28-derived signals at the level of the slp76 signalosome [13].”
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 [13]
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“This was of particular interest because a recent report suggested that in rat T cells CD28SA induced IL-2 production might not require PI3K activity [12].”
BackgroundResultInfluentialManipulation of regulatory T-cell number and function with CD28-specific monoclonal antibodies
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- Authors
- Dennehy, K. M., Elias, F., Na, S.-Y., Fischer, K.-D., Hünig, T., & Lühder, F.
- Affiliations
- University of Würzburg (DE)
- Universität Ulm (DE)
- Institute of Virology and Immunobiology, University of Würzburg , Würzburg ,
- Corresponding author
- Elias, Fernando
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-02-01
- Volume
- 178
- Issue
- 3
- Pages
- 1363-1371
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2121251204
- Cited by
- 45
- References
- 66
- Citations by year
- 2026: 2 · 2024: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 3 · 2013: 3 · 2012: 4
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- CD28 signaling, Vav1, SLP-76, T cell receptor signaling, T cell costimulation, signalosome, calcium flux, IL-2 production, Tec kinase, ZAP-70, T cell proliferation
- MeSH terms
- Animals, Humans, Phosphoproteins, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, CD28 Antigens, Jurkat Cells, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Rats, Proto-Oncogene Proteins c-vav
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