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.

Keywords: CD4+ T cells; IL-17; IL-2; JAK/STAT; autoimmunity; endosome traffic; glucose; glutamine; interferon; kynurenine; lysosome; mTOR; metabolism; systemic lupus erythematosus; tryptophan.

Figure 1

Endosomal trafficking and recycling pathways are illustrated. Cell membrane proteins are endocytosed, then the internalized cargoes converge into a common early endosome. There are two pathways of recycling back to the plasma membrane: (1) the rapid-recycling pathway, directly from the early endosome, and (2) the slow-recycling pathway, via the recycling endosome. The cargoes can be released out of the cell as exosomes through the late endosome or the multi-vesicular body. Some cargoes from endosomes are routed to the lysosome for degradation. Rab GTPases play important roles in receptor recycling, including endocytosis, intracellular vesicle trafficking, and exosome secretion. Key Rab family proteins are highlighted.

Figure 2

Metabolic abnormalities in SLE T cells and how they contribute to the signaling pathways that control IL-2 and IL-17 production. CD71, which controls the iron flux, is increased in SLE T cells. In place of the CD3ζ protein, FcεRIγ is substituted. In SLE T cells, FcεRIγ recruits Syk instead of ZAP-70. FcεRIγ–Syk interaction is significantly stronger than CD3ζ–ZAP-70 interaction, resulting in higher calcium influx. CD38, which is increased in SLE T cells, converts NAD⁺ into cADPR, which mediates calcium-mobilizing activity. GLUT1, a glucose transporter, and ASCT2, a glutamine transporter, are increased in SLE T cells, and the resulting glycolysis, glutaminolysis, and the TCA cycle are shown. The effects of these metabolites on pathways that affect IL-2 and IL-17 production are shown. Red arrows, increased in SLE T cells. Blue arrows, decreased in SLE T cells.

Figure 3

Receptors that contribute to NAD⁺ synthesis pathways in T cells and how NAD⁺ affects IL-2 and IL-17 production. NAD⁺ synthesis pathways shown are: (1) de novo pathway, (2) Preiss–Handler pathway, (3) nucleoside pathway, and (4) salvage pathway. The kynurenine transported by System L amino acid transporters, which are heterodimers of CD98 and LAT1 contribute to the de novo pathway. CD73 has dual enzymatic functions, (1) cleaving NAD⁺ to NMN and (2) hydrolyzing NMN to NR, which both contribute to the nucleoside pathway after being imported into the cell by the nicotinamide mononucleotide transporter, Slc12a8 and equilibrative nucleoside transporter (ENT), respectively. CD38 and CD157 are ADP-ribosyl cyclases, converting NAD⁺ into cADPR and hydrolyzing cADPR to form ADPR. The NAD-dependent histone deacetylases, sirtuins, and their effects on IL-2 and IL-17 production are shown. Red arrows, increased in SLE T cells. Blue arrows, decreased in SLE T cells.