Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses

Abstract

SummaryExpansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ T cell effector function.

A C3(H20) recycling pathway is a component of the intracellular complement system

“…Finally, our data and other recent investigations now broaden the role of the newly discovered ICS (4,11). The finding of a C3(H 2 O)-recycling pathway has important implications for our understanding of basic processes the cell utilizes for homeostasis and defense.…”

“…Further, CTSLdriven C3a generation is required for CD4 + T cell survival, and shuttling of C3a to the cell surface is necessary for Th1 effector cell differentiation and proinflammatory cytokine production (4). In a follow-up to this study, the Kemper group demonstrated that intracellular C3b generation (and autocrine CD46 stimulation) is required for metabolic reprogramming that allows Th1 cell activation and contraction (11). Further, this group suggested that such reprogramming also provides for a novel "complement-metabolism-inflammasome" axis (12).…”

“…Whether this predicted NLS mediates FH nuclear targeting and additional roles of FH in the nucleus are interesting areas for investigation. Notably, another member of the RCAcontaining protein family, CD46, also contains a NLS in its cytoplasmic tail and targets to the nucleus (11,28).…”

“…Despite growing evidence indicating the importance of intracellular C3 stores in human T cell homeostasis (4,8,11,12), the source and composition of these stores have not been rigorously investigated. Initially, we set out to characterize the composition of the intracellular C3 stores.…”

T cell metabolism drives immunity

“…The extent to which FAO occurs in effector T cells is likely to be highly context dependent, in part due to the heterogeneity of this population of cells during an immune response. Studies using animal models of graft versus host disease (GvHD) have found that alloreactive T cells increase fatty acid uptake and enhance FAO compared with other effector T cells (Gatza et al, 2011;Byersdorfer et al, 2013;Glick et al, 2014). Suppressing Akt during activation can induce a metabolic profile suggestive of FAO utilization (Crompton et al, 2015), and culturing CD8 effector T cells in low glucose enhances FAO .…”