Intracellular complement - the complosome - in immune cell regulation

Abstract

The complement system was defined over a century ago based on its ability to "complement" the antibody-mediated and cell-mediated immune responses against pathogens. Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity. The complement system consists of over 50 blood-circulating, cell-surface expressed and intracellular proteins. It is key in the recognition and elimination of invading pathogens, also in the removal of self-derived danger such as apoptotic cells, and it supports innate immune responses and the initiation of the general inflammatory reactions. The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system, however, recent experimental and clinical evidences have demonstrated that "local" tissue and surprisingly intracellular complement (the complosome) activation impacts on normal cell physiology. This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism. We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses.

Fig. 1

The complosome in T cell regulation. In the resting state (homeostasis), T lymphocytes have intracellular stores of C3, C5 and cathepsin L (CTSL). C3 can be expressed by T cells or taken up from serum (recycling pathway). Small amounts of C3(H₂O) are constantly cleaved by CTSL into C3a and C3b. Intracellular C3a engages intracellular C3aR to induce low level mTOR activation to sustain cell survival. T cell receptor (TCR) stimulation (effector response) induces the translocation of C3 and C3 activation fragments and CTSL to the cell surface where C3a and C3b fragments signal in autocrine activation though C3aR and CD46, respectively. Upon CD46 activation, predominant CD46-CYT-2 expression switches to increased CD46-CYT-1 expression. CYT-1 is then cleaved by γ-secretase (not shown) to allow for CYT-1 nuclear translocation which drives expression of LAMTOR5, the glucose transporter GLUT1 (SLC7A5) and the amino acid transporter LAT1 (SLC2A1). The activation of the C3 complosome cumulates in mTORC activation, nutrient influx, and augmented glycolysis and oxidative phosphorylation (in violet). Furthermore, CD46 stimulation induces gene expression of NLRP3 and IL1 B to prime the NLRP3 inflammasome. CD46 also induces intracellular C5 activation and C5a generation via yet unknown mechanisms. Intracllular C5a then engages the intracellular C5aR1 to amplify ROS production which triggers the assembly of the NLRP3 inflammasome and subsequent IL-1β production for optimal Th1 induction (in green). During the contraction phase of Th1 response, CD46-CYT-2 tail isoform expression becomes dominant again and, in conjunction with IL-2R signalling, induces IL-10 co-production in Th1 cells and the transition into a (self)regulatory Th1 contraction phase. The switch to IL-10 is accompanied by C5a secretion to the cell surface which engages surface expressed C5aR2 that blocks C5aR1 signaling and therefore negatively controls Th1 responses. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Suggestions on the potential impact of complosome-derived and/or pathogen-shunted intracellular complement on key cell processes during the host/pathogen interaction. Pathogens trigger an array of responses when interacting with complement during cell infection processes − some of which are beneficial for the microbe and some of which support host protection. For example, infection of human papillomavirus (HPV) triggers globular C1q receptor signaling (gC1qR) which leads to mitochondrial dysfunction and apoptosis (1). Opsonized bacteria trigger mitochondrial antiviral signaling which increases the expression of AP-1- and NF-κB −controlled genes and proinflammatory cytokine responses. C3-opsonized viruses, on the other hand, are targeted for degradation via the proteosome (2). Opsonized Listeria is also targeted in an intracellulr complement-dependent fashion for degradation after cell entry through v-set immunoglobulin domain containing 4 (VSIG4)-driven autophagosome formation (3). Supporting viral and bacterial propagation, gC1R signaling on mitochondria was also shown to block retinoic acid-inducible gene I (RIG-I) activation in a process that promoted the replication of vesicular stomatitis virus (4), while opsonized Klebsiella and other species use vitronection to gain entry in non-phagocytic cells (5). Although in most of these processes, complement fragments were ‘dragged’ into the cell by microbes, we propose that there will also be (subsequent) interactions of invading intracellular pathogens with components the complosome, for example C3 and C5 activation fragments (6). In line with the ‘scheme’ observed for the role of serum-derived complement, we further predict that in some cases the complosome will mediate clearance pf the pathogen while in other cases, it will be utilized by the pathogen to promote its survival.