Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation
05.12.2013
Liszewski MK, Kolev M, Le Friec G, Leung M, Bertram PG, Fara AF, Subias M, Pickering MC, Drouet C, Meri S, Arstila TP, Pekkarinen PT, Ma M, Cope A, Reinheckel T, Rodriguez de Cordoba S, Afzali B, Atkinson JP, Kemper C.
Immunity. 2013 Dec 12;39(6):1143-57
Processing of the complement key component, C3, into activation fragments C3a and C3b has been thought to be confined to the extracellular space. This paper shows that C3 activation also occurres intracellularly. The protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b in the secretory lysosomes of T-cells. 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-g 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.
