Emerging functions of thrombospondin-1 in immunity

Abstract

Thrombospondin-1 is a secreted matricellular glycoprotein that modulates cell behavior by interacting with components of the extracellular matrix and with several cell surface receptors. Its presence in the extracellular matrix is induced by injuries that cause thrombospondin-1 release from platelets and conditions including hyperglycemia, ischemia, and aging that stimulate its expression by many cell types. Conversely, rapid receptor-mediated clearance of thrombospondin-1 from the extracellular space limits its sustained presence in the extracellular space and maintains sub-nanomolar physiological concentrations in blood plasma. Roles for thrombospondin-1 signaling, mediated by specific cellular receptors or by activation of latent TGFβ, have been defined in T and B lymphocytes, natural killer cells, macrophages, neutrophils, and dendritic cells. In addition to regulating physiological nitric oxide signaling and responses of cells to stress, studies in mice lacking thrombospondin-1 or its receptors have revealed important roles for thrombospondin-1 in regulating immune responses in infectious and autoimmune diseases and antitumor immunity.

Keywords: Antigen presenting cells; Antitumor immunity; Autoimmune disease; CD47; Natural killer cells; T cells.

Figure 1.

Thrombospondin-1 regulates immune cell functions of T cells, natural killer (NK) cells, dendritic cells (DC), and macrophages (MΦ) by initiating signaling mediated by several cell surface receptors, by activating secreted latent TGFβ (LTGFβ), and by incorporation into supramolecular attack particles (SMAPs) produced by CD8 T cells and NK cells that mediate sustained target cell killing.

Figure 2.

Proposed bridging mechanisms by which thrombospondin-1 facilitates the phagocytic clearance of apoptotic cells by macrophages and neutrophils.