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Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation
- Source :
- Immunity
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Summary Complement 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.<br />Graphical Abstract<br />Highlights • Complement C3 is activated intracellularly in human T cells by cathepsin L • Intracellular C3 activation mediates cell survival and Th1 induction • Increased intracellular C3 activation underlies T effector dysregulation in arthritis • Patients with serum C3-deficiency retain intracellular C3a generation
- Subjects :
- Adult
CD4-Positive T-Lymphocytes
Cell Survival
Cathepsin L
Cellular differentiation
Immunology
B-Lymphocyte Subsets
chemical and pharmacologic phenomena
Biology
Article
Cell Line
Proinflammatory cytokine
Arthritis, Rheumatoid
03 medical and health sciences
0302 clinical medicine
Extracellular
Homeostasis
Humans
Immunology and Allergy
Child
Autocrine signalling
Complement Activation
030304 developmental biology
0303 health sciences
Innate immune system
CD46
Cell Differentiation
Complement C3
3. Good health
Complement system
Cell biology
Infectious Diseases
Gene Expression Regulation
Complement C3b
Complement C3a
Intracellular
030215 immunology
Subjects
Details
- ISSN :
- 10747613
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Immunity
- Accession number :
- edsair.doi.dedup.....c67bc2fa3c407626b335b9fe296f501d