CD28 is expressed by macrophages with anti‐inflammatory potential and limits their T‐cell activating capacity
Abstract
CD28 expression is generally considered to be T lymphocyte specific. We have previously shown CD28 mRNA expression in M-CSF-dependent anti-inflammatory monocyte-derived macrophages (M-MØ), and now demonstrate that CD28 cell surface expression is higher in M-MØ than in GM-CSF-dependent macrophages, and that macrophage CD28 expression is regulated by MAFB and activin A. In vivo, CD28 was found in tumor-associated macrophages and, to a lower extent, in pro-inflammatory synovial fluid macrophages from rheumatoid arthritis patients. Analysis of mouse macrophages confirmed Cd28 expression in bone-marrow derived M-MØ. Indeed, anti-CD28 antibodies triggered ERK1/2 phosphorylation in mouse M-MØ. At the functional level, Cd28KO M-MØ exhibited a significantly higher capacity to activate the OVA-specific proliferation of OT-II CD4 + T cells than WT M-MØ, as well as enhanced LPS-induced IL-6 production. Besides, the Cd28KO M-MØ transcriptome was significantly different from WT M-MØ regarding the expression IFN response, inflammatory response, and TGF-β signaling related gene sets. Therefore, defective CD28 expression in mouse macrophages associates to changes in gene expression profile, what might contribute to the altered functionality displayed by Cd28KO M-MØ. Thus, CD28 expression appears as a hallmark of anti-inflammatory macrophages and might be a target for immunotherapy.
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CD28 has been reported in anti-inflammatory macrophages, where it was proposed as a marker of suppressive or regulatory macrophage polarization rather than conventional lymphocyte activation.
“In peripheral myeloid biology, CD28 has been reported in anti-inflammatory macrophages, where it was proposed as a marker of suppressive or regulatory macrophage polarization rather than conventional lymphocyte activation [43].”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [43]
CD28 expression in a myeloid cell may mark an immunoregulatory state rather than a lineage error or sequencing artifact.
“This precedent does not prove that microglial CD28 has the same function, but it makes the Ayata et al. finding more plausible: CD28 expression in a myeloid cell may mark an immunoregulatory state rather than a lineage error or sequencing artifact.”
From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [43]
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- Authors
- Estrada‐Capetillo, L., Aragoneses‐Fenoll, L., Domínguez‐Soto, Á., Fuentelsaz‐Romero, S., Nieto, C., Simón‐Fuentes, M., Alonso, B., Portolés, P., Corbí, A. L., Rojo, J. M., & Puig‐Kröger, A.
- Affiliations
- Hospital General Universitario Gregorio Marañón (ES)
- Unidad de Inmunología Celular, Centro Nacional de Microbiología Instituto de Salud Carlos III Madrid Spain
- Centro de Investigaciones Biológicas Margarita Salas (ES)
- Unidad de InmunoMetabolismo e Inflamación, Instituto de Investigación Sanitaria Gregorio Marañón Hospital General Universitario Gregorio Marañón Madrid Spain
- Centro de Investigaciones Biológicas Margarita Salas Madrid Spain
- Corresponding author
- Puig‐Kröger, Amaya
- ORCID
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2020-11-24
- Volume
- 51
- Issue
- 4
- Pages
- 824-834
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W3103333209
- Cited by
- 22
- References
- 61
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 6 · 2023: 2 · 2022: 2
- FWCI
- 0.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CD28, macrophages, anti-inflammatory macrophages, MAFB, activin A, tumor-associated macrophages, T cell activation, ERK1/2 phosphorylation, interleukin-6, TGF-beta signaling, macrophage transcriptome, immunotherapy targets
- MeSH terms
- Animals, Arthritis, Rheumatoid, Cells, Cultured, Humans, Inflammation, Lymphocyte Activation, Macrophages, Mice, Inbred C57BL, T-Lymphocytes, Signal Transduction, Gene Expression, CD28 Antigens, Mice, Knockout, Gene Expression Profiling, Activins, MafB Transcription Factor, Mice
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