Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

Abstract

SummaryComplement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While “tonic” intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes

“…C3 endogenously expressed by many different cell types 19 is cleaved upon complement activation into the anaphylatoxin C3a and the opsonin C3b. In serum, surface-deposited C3b will be further cleaved into iC3b by the serine protease factor I.…”

“…This indicates that FH is stable within the apoptotic cells over a period of at least 44 h. The lysosomal cysteine protease cathepsin L (CTSL) cleaves C3 into C3a and C3b upon T-cell activation. 19 Upon apoptosis induction, cathepsins are released into the cytosol and remain functional as the cytosolic pH decreases. 20 To investigate a potential effect of FH on CTSL-mediated cleavage of C3, a fixed concentration of activated CTSL was incubated with 125 I-labeled C3 in the presence of increasing concentrations of FH.…”

“…C3 is stored in the endosomes of T cells and may be cleaved into biologically active C3a and C3b upon T-cell activation by the lysosomal cysteine protease CTSL. 19 CTSL and other lysosomal proteases are released into the cytosol upon apoptosis induction. 23 The fact that FH does not become degraded within the apoptotic cells implies that it remains functional after internalization.…”

Production of complement components by cells of the immune system

“…This intracellular C3a is subsequently able to bind the intracellular C3aR and signals via mTOR [33]. Besides intracellular C3aR, a role was assigned more recently to intracellular C5aR1 cells in CD4 …”

Molecular cloning and expression analysis of Pleurodeles waltl complement component C3 under normal physiological conditions and environmental stresses

“…This system involves a family of proteins that are mainly synthetized by the liver (Walport, 2001a,b), though lower levels can be produced by other cell types. Complement activation can be achieved in the extracellular space through three pathways (classical, lectins or alternative) and intracellularly via a cathepsin-dependent mechanism (Liszewski et al, 2013).…”