CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling
Abstract
CD28 is one of the most important co-stimulatory receptors necessary for full T lymphocyte activation. By binding its cognate ligands, B7.1/CD80 or B7.2/CD86, expressed on the surface of professional antigen presenting cells (APC), CD28 initiates several signalling cascades, which qualitatively and quantitatively support T cell receptor (TCR) signalling. More recent data evidenced that human CD28 can also act as a TCR-independent signalling unit, by delivering specific signals, which regulate the expression of pro-inflammatory cytokine/chemokines. Despite the enormous progresses made in identifying the mechanisms and molecules involved in CD28 signalling properties, much remains to be elucidated, especially in the light of the functional differences observed between human and mouse CD28. In this review we provide an overview of the current mechanisms and molecules through which CD28 support TCR signalling and highlight recent findings on the specific signalling motifs that regulate the unique pro-inflammatory activity of human CD28.
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In a plaque-associated microglial niche, CD28 may participate in a local feedback system that limits excessive inflammatory escalation while preserving protective plaque-associated functions.
“In a plaque-associated microglial niche, CD28 may participate in a local feedback system that limits excessive inflammatory escalation while preserving protective plaque-associated functions [20,41].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [41]
Without CD28 co-stimulation, antigen recognition alone may lead to incomplete activation, tolerance, or anergy.
“Without this co-stimulatory context, antigen recognition alone may lead to incomplete activation, tolerance, or anergy.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [41]
CD80 and CD86 are potent T-cell co-stimulators, and CD28 tunes the quality, duration, and metabolic consequences of immune activation.
“Early studies in the 1990s established CD80 and CD86 as potent T-cell co-stimulators, while later reviews refined the view of CD28 as a receptor that does not simply “turn on” T cells, but tunes the quality, duration, and metabolic consequences of immune activation [40,41,42].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [41]
CD28 is a co-stimulatory receptor on T cells; engagement by CD80 and CD86 on antigen-presenting cells provides a second signal supporting T-cell activation, survival, proliferation, cytokine production, and differentiation.
“In classical immunology, CD28 is best known as a co-stimulatory receptor on T cells. Its engagement by the B7-family ligands CD80 and CD86 on antigen-presenting cells provides a second signal that supports T-cell activation, survival, proliferation, cytokine production, and differentiation.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [41]
Cites
Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412
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The CD28 Signaling Pathway Regulates Glucose Metabolism
Frauwirth, K. A., Riley, J. L., Harris, M. H., Parry, R. V., Rathmell, J. C., Plas, D. R., Elstrom, R. L., June, C. H., & Thompson, C. B. (2002) · Immunity · doi:10.1016/s1074-7613(02)00323-0 · Cited by 1,475 · see citing works
Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.
Rudd, C. E., & Schneider, H. (2003) · Nature Reviews Immunology · doi:10.1038/nri1131 · Cited by 392 · see citing works
Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines
Kane, L. P., Andres, P. G., Howland, K. C., Abbas, A. K., & Weiss, A. (2001) · Nature Immunology · doi:10.1038/83144 · Cited by 316 · see citing works
Lin, C., & Hünig, T. (2003) · European Journal of Immunology · doi:10.1002/eji.200323570 · Cited by 184 · see citing works
Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies
Waibler, Z., Sender, L. Y., Merten, C., Hartig, R., Kliche, S., Gunzer, M., Reichardt, P., Kalinke, U., & Schraven, B. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001708 · Cited by 79 · see citing works
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Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?
Fulop, T., Larbi, A., Dupuis, G., Le Page, A., Frost, E. H., Cohen, A. A., Witkowski, J. M., & Franceschi, C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01960 · Cited by 1,364 · see citing works
Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis?
Chmiel, J., Gawełczyk, W., Soczyńska, J., & Leszek, J. (2026) · Cells · doi:10.3390/cells15131151
“In a plaque-associated microglial niche, CD28 may participate in a local feedback system that limits excessive inflammatory escalation while preserving protective plaque-associated functions [20,41].”
- Authors
- Porciello, N., & Tuosto, L.
- Affiliations
- Istituto Pasteur (IT)
- Corresponding author
- Tuosto, Loretta
- Venue
- Cytokine & Growth Factor Reviews
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 28
- Pages
- 11-19
- ISSN
- 1359-6101 (ISSN-L)
- OpenAlex
- W2300738269
- Cited by
- 61
- References
- 6
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 12 · 2019: 4 · 2018: 7 · 2017: 7 · 2016: 2
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cytokine & Growth Factor Reviews (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- CD28, T cell activation, T cell receptor signaling, B7-1 (CD80), B7-2 (CD86), antigen-presenting cells, inflammatory cytokines, chemokines
- MeSH terms
- Animals, Humans, Lymphocyte Activation, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Cytokines, CD28 Antigens
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