Figure 6.

The role of the complosome in Th1 cell induction and contraction. (a) T cell receptor activation and CD28 costimulation of resting T cells induce the intracellular generation of the CD46 ligand C3b by CTSL cleavage and the increased expression of CD46 isoforms bearing CYT-1. Nuclear translocation of CYT-1 upon autocrine CD46 activation upregulates CD25 and CD132 gene expression, allowing for the enhanced IL-2 receptor signaling important for Th1 induction while decreasing CD127 gene expression. Autocrine CD46 CYT-1-driven signals also induce expression of the glucose transporter GLUT1 and the AA channel LAT1, allowing for increased glucose and AA influx. In parallel, CD46 CYT-1-mediated signals induce increased expression of LAMTOR5 and, via this the assembly of the lysosome-based mTORC1 machinery, which senses AA influx and drives the high levels of glycolysis and OXPHOS required for IFN-γ secretion. CD46-mediated signals also trigger increased intracellular C5a generation, which supports the mitochondrial metabolic activity and ROS production critical to normal Th1 induction. C5aR1-driven ROS production and mTORC1 activity also activate the NLRP3 inflammasome in TCR-stimulated T cells, a process that supports Th1 expansion via IL-1β functioning in an autocrine fashion. (b) During Th1 contraction and induction of IL-10 coexpression, CD46 isoform expression reverts to a CYT-2-predominant pattern (through an unknown mechanism), and this development, in conjunction with IL-2 receptor signaling (also through an unknown mechanism), results in reduced expression of GLUT1 and LAT1, downregulation of glycolysis and OXPHOS, and reduced IFN-γ production. Moreover, autocrine engagement of the surface-expressed C5aR2 via C5a or C5a-desArg secreted upon T cell activation contributes to negative regulation of mitochondrial activity and reduction of ROS (through inhibition of intracellular C5aR1 activity and/or a yet-undefined mechanism). ‘Red’ arrows denote inhibitory activities of receptors and ‘dashed’ lines denote observed effects with the underlying mechanisms not yet defined. Abbreviations: AA, amino acids; C5a-desArg, “desarginated” form of C5a; CTSL, cathepsin L; GLUT1, glucose transporter 1; LAMTOR5, late endosomal-lysosomal adaptor, MAPK, and mTOR activator 5; LAT1, neutral amino acid transporter 1; mTORC1, mechanistic target of rapamycin complex 1; NLRP3, NACHT-, leucine-rich repeat–, and pyrin domain–containing protein 3; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCR, T cell receptor.