CD28 is expressed by macrophages with anti‐inflammatory potential and limits their T‐cell activating capacity

• Published in: European journal of immunology 2021-04, Vol.51 (4), p.824-834
• Main Authors: Estrada‐Capetillo, Lizbeth, Aragoneses‐Fenoll, Laura, Domínguez‐Soto, Ángeles, Fuentelsaz‐Romero, Sara, Nieto, Concha, Simón‐Fuentes, Miriam, Alonso, Bárbara, Portolés, Pilar, Corbí, Angel L., Rojo, Jose M., Puig‐Kröger, Amaya
• Format: Article
• Language: English
• Subjects: Activin; Activins - genetics; Activins - immunology; Activins - metabolism; Animals; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Bone marrow; CD28 antigen; CD28 Antigens - genetics; CD28 Antigens - immunology; CD28 Antigens - metabolism; CD28 expression; CD4 antigen; Cell proliferation; Cell surface; Cells, Cultured; Gene expression; Gene Expression - immunology; Gene Expression Profiling - methods; Humans; Immunotherapy; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interferon; Lipopolysaccharides; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes T; Macrophage; Macrophage polarization; Macrophages; Macrophages - immunology; Macrophages - metabolism; MafB Transcription Factor - genetics; MafB Transcription Factor - immunology; MafB Transcription Factor - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Phosphorylation; Rheumatoid arthritis; Signal Transduction - genetics; Signal Transduction - immunology; Synovial fluid; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcriptomes; T‐cell activation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.202048806

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. CD28 was found on anti‐inflammatory M‐CSF‐dependent macrophages, and detected on tissue‐resident macrophages under homeostatic and pathological conditions. Macrophage CD28 expression is dependent on MAFB and inhibited by IFN‐γ and modifies the functional and gene profile of bone marrow derived murine macrophages. Thus, CD28 appears as a hallmark of anti‐inflammatory macrophages.