Endosome Traffic Modulates Pro-Inflammatory Signal Transduction in CD4+ T Cells—Implications for the Pathogenesis of Systemic Lupus Erythematosus

Abstract

Endocytic recycling regulates the cell surface receptor composition of the plasma membrane. The surface expression levels of the T cell receptor (TCR), in concert with signal transducing co-receptors, regulate T cell responses, such as proliferation, differentiation, and cytokine production. Altered TCR expression contributes to pro-inflammatory skewing, which is a hallmark of autoimmune diseases, such as systemic lupus erythematosus (SLE), defined by a reduced function of regulatory T cells (Tregs) and the expansion of CD4+ helper T (Th) cells. The ensuing secretion of inflammatory cytokines, such as interferon-γ and interleukin (IL)-4, IL-17, IL-21, and IL-23, trigger autoantibody production and tissue infiltration by cells of the adaptive and innate immune system that induce organ damage. Endocytic recycling influences immunological synapse formation by CD4+ T lymphocytes, signal transduction from crosslinked surface receptors through recruitment of adaptor molecules, intracellular traffic of organelles, and the generation of metabolites to support growth, cytokine production, and epigenetic control of DNA replication and gene expression in the cell nucleus. This review will delineate checkpoints of endosome traffic that can be targeted for therapeutic interventions in autoimmune and other disease conditions.

Extracellular Vesicles in Triple–Negative Breast Cancer: Immune Regulation, Biomarkers, and Immunotherapeutic Potential

“…The Rab GTPases maintain intracellular trafficking, regulating the traffic between organelles by recruiting effector proteins. Therefore, Rab GTPases are considered the "master regulators" of intracellular trafficking [41]. During early apoptosis in cells, cells secrete apoptotic exosome-like vesicles (AEVs).…”

“…As a result, the cell receives nutrients and energy. Second, amphisomes can also fuse with the plasma membrane, leading to the release of exosomes outside of the cell via exophagy [41]. Both MPs and exosomes play crucial roles, not only in maintaining homeostasis but also in the progression and development of various pathophysiological conditions, for example, cancer, due to the transfer of bioactive cargo [43].…”