RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 31 December 2013; doi:10.1038/nri3603 INNATE IMMUNITY The inside story on complement activation The evolutionarily ancient comple- inconsistent with de novo protein — the production of interferon-γ ment system might have started life production, so the authors looked (IFNγ) and interleukin-17 was sig- as an intracellular activation pathway for a potential role of endogenous nificantly decreased but could be par- rather than as a liver-derived serum proteases. They showed that rest- tially rescued by the addition of C3a. effector cascade. Other recent studies ing human T cells express mRNA Cytokine production was not affected have suggested the importance of encoding cathepsin L (CTSL), and in serum-free medium or in the T cell-derived local complement acti- that CTSL cleaves C3 into biologi- presence of a C3 convertase inhibitor, vation in the autocrine stimulation of cally active C3a and C3b fragments which shows that the CTSL-mediated T helper 1 (T 1) cell responses, but in vitro. C3 and CTSL were found to C3 activation pathway is sufficient H intracellular Claudia Kemper, John Atkinson and be colocalized in resting T cells in for autocrine C3aR-induced T cell colleagues are the first to show that C3a the endoplasmic reticulum (ER) and effector function in humans. the C3 activation products C3a and generation ER-derived secretory vesicles. The in vivo relevance of this C3b can be generated intracellularly … is both Intracellular C3a was detected in pathway was shown in synovial fluid in human CD4+ T cells. resting T cells, and the increase in CD4+ T cells from patients with juve- Activation of mouse T cells is upregulated intracellular C3a levels observed after nile idiopathic arthritis. The T cells thought to induce the expression of and antibody-mediated T cell activation had increased levels of intracellular C3, factor B and factor D proteins, translocated to could be prevented by a cell-perme- C3a, mTOR activation and IFNγ pro- resulting in extracellular assembly the cell surface able CTSL inhibitor. C3a, C3b, CTSL duction compared with peripheral of a C3 convertase and cleavage of and C3a receptor (C3aR) were pre- blood T cells from the same patient C3. However, the rapid generation after T cell sent on the surface of activated but or from a healthy donor. The addi- of C3a and C3b by human T cells is activation not resting T cells, and C3a levels on tion of a CTSL inhibitor to patient the T cell exterior could be decreased synovial T cell cultures ‘normalized’ both by the cell-permeable CTSL all of these parameters in a dose- inhibitor and by a cleavage-blocking dependent manner. So, the uncon- CTSL-specific antibody. So, the data trolled T cell activity in this disease indicate that a system for ‘tonic’ might be due, at least in part, to the intracellular C3a generation by CTSL deregulation of CTSL‑mediated C3a in resting T cells is both upregulated generation. and translocated to the cell surface This demonstration of intracel- EXCLUSIVE: after T cell activation. lular complement activation has CTSL inhibition in resting and important implications for how SHOCK activated T cells decreased mam- the complement pathway might malian target of rapamycin (mTOR) interact with other components of phosphorylation and cell survival, innate immunity, such as intracel- NEW as did the inhibition of intracellular lular pattern recognition receptors. C3aR expression or signalling. Cell Furthermore, cells of myeloid, COMPLEMENT viability could not be rescued by lymphoid and non-myeloid, non- extracellular C3a supplementation, lymphoid origin were all shown to which indicates that intracellular generate intracellular C3a, so the PATHWAY C3a–C3aR signalling is required authors suggest that intracellular for T cell survival. Further stud- complement activation might be a ies showed that cell surface C3aR general phenomenon with potential engagement after T cell activation roles in other basic cell processes. drives effector function. When T cells Kirsty Minton were activated in the presence of a ORIGINAL RESEARCH PAPER Liszewski, M. K. low concentration of CTSL inhibitor et al. Intracellular complement activation sustains — which decreases cell surface C3a T cell homeostasis and mediates effector NPG differentiation. Immunity 39, 1143–1157 (2013) levels without affecting cell viability NATURE REVIEWS | IMMUNOLOGY VOLUME 14 | FEBRUARY 2014 © 2013 Macmillan Publishers Limited. All rights reserved.