CD9 Tetraspanin: A New Pathway for the Regulation of Inflammation?

Abstract

CD9 belongs to the tetraspanin superfamily. Depending on the cell type and associated molecules, CD9 has a wide variety of biological activities such as cell adhesion, motility, metastasis, growth, signal transduction, differentiation, and sperm-egg fusion. This review focuses on CD9 expression by hematopoietic cells and its role in modulating cellular processes involved in the regulation of inflammation. CD9 is functionally very important in many diseases and is involved either in the regulation or in the mediation of the disease. The role of CD9 in various diseases, such as viral and bacterial infections, cancer and chronic lung allograft dysfunction, is discussed. This review focuses also on its interest as a biomarker in diseases. Indeed CD9 is primarily known as a specific exosome marker however, its expression is now recognized as an anti-inflammatory marker of monocytes and macrophages. It was also described as a marker of murine IL-10-competent Breg cells and IL-10-secreting CD9⁺ B cells were associated with better allograft outcome in lung transplant patients, and identified as a new predictive biomarker of long-term survival. In the field of cancer, CD9 was both identified as a favorable prognostic marker or as a predictor of metastatic potential depending on cancer types. Finally, this review discusses strategies to target CD9 as a therapeutic tool. Because CD9 can have opposite effects depending on the situation, the environment and the pathology, modulating CD9 expression or blocking its effects seem to be a new promising therapeutic strategy.

Keywords: CD9; cancer; hematopoietic cells; hypersensitivity; infections; inflammation; lung allograft dysfunction; tetraspanin.

Figure 1

CD9 regulates hematopoietic stem cells differentiation. CD9 is expressed by hematopoietic stem cells and is involved in the differentiation of the megakaryocytic, B-lymphoid and myeloid lineages. CD9 expressed in stromal cells influences physical interactions with hematopoietic cells.

Figure 2

CD9 regulates myeloid lineages. CD9 is expressed on the plasma membrane of different myeloid lineages and is associated with MHC-II and integrins on eosinophils and with FcRs on basophils, platelets, mast cells and macrophages. CD9 activates cells degranulation and cytokines secretion and is involved in cytokine-mediated chemotactic responses. Finally, CD9 regulates inflammation, allowing eosinophils to stimulate CD4⁺ T-cell activation and induce macrophage activation.

Figure 3

CD9 is necessary for dendritic cell activity. On human DCs, CD9 co-localizes with CD81 and FcεRI, and crosslinking with FcεRI induces IL-10 secretion. CD9 is also physically associated with MHC-II molecules and CD38 in TEMs, and the integrity of these lipid rafts is necessary for antigenic presentation by DCs and dexosome release. CD9 is now mostly known as a specific exosome marker.

Figure 4

CD9 regulates lymphoid lineages. On conventional B cells, CD9 is physically linked to CD19 through the tetraspan CD81. This association induces B cell differentiation by modulation of integrin activity and allows B cell activities such as antibodies production. CD9 expression also promotes follicular dendritic cell adhesion-inducing survival. CD9 is shown to be involved in the enhancement and maintenance of IL-10 secretion and has been identified as a marker of Breg cells. On T cells, CD9 is associated with CD3, CD4, CD2, CD29, CD44 and more prominently with CD5 and CD28. CD9/CD28 co-ligation induces naïve T cell activation and differentiation into TH2 and apoptosis of activated T cells. CD9 also supports integrin-mediated signaling and can induce membrane-phosphatidylserine exposure.

Figure 5

CD9 promotes adhesion and extravasation of leucocyte. CD9 co-localizes with adhesion molecules ICAM-1 and VCAM-1 at the apical endothelial cell surface to promote endothelial–leucocyte adhesion and enhance extravasation and transmigration of leucocytes to the inflammatory site.

Figure 6

Dual role of CD9 in human diseases. CD9 can either enhance or inhibit pathogenic conditions through TEMs in human diseases. Each color frame refers to implied cells in pathogenic conditions: purple stands for dendritic cells, pink for cancer cells, green for B cells, yellow for epithelial cells, and red for monocytes.