Human plasma C3 is essential for the development of memory B, but not T, lymphocytes

Jiménez-Reinoso, Anaïs; Marín, Ana V.; Subias, Marta; López-Lera, Alberto; Román-Ortiz, Elena; Payne, Kathryn; Cindy, S.; Arbore, Giuseppina; Kolev, Martin; Freeley, Simon; Kemper, Claudia; Tangye, Stuart G.; Fernández-Malavé, Edgar; Córdoba, Santiago Rodrı́guez de; López-Trascasa, Margarita; Regueiro, José R.

doi:10.1016/j.jaci.2017.09.037

Cited by 21 publications

(23 citation statements)

References 25 publications

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“…39 Human plasma C3 is not essential for the development of T cells. 40 However, our results demonstrated that C3 derived from HSCs had a suppressive effect on T-cell proliferation. The inconsistent effect of C3 on immune response may be due to other cell populations or coexisting factors in the local inflammatory environment, which could directly or indirectly modulate C3 signaling on immune cells.…”

Section: Discussionmentioning

confidence: 50%

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

Huang

et al. 2020

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Objective: Hepatic stellate cells (HSCs) are the important players in liver cirrhosis and liver cancer. They also act as critical mediators of immunosuppression in hepatocellular carcinoma (HCC). In this study, we hypothesized that HSCs promote HCC progression via C3. Methods: C3 in HSCs was knocked down using a shRNA retroviral plasmid. The conditioned medium from HSCs or shC3 HSCs (knockdown of C3 by shRNA in HSCs) was collected to detect their effects on bone marrow (BM) and T cells (including expansion and apoptosis) in vitro, and in an HCC in situ model in mice. Results: We found that HSCs promoted T-cell apoptosis and decreased their proliferation, inhibited dendritic cell (DC) maturation, and induced myeloid-derived suppressor cell (MDSC) expansion through the C3 pathway in vitro. In addition, the knockdown of C3 suppressed HSC-promoted HCC development in the orthotopic transplantation tumor model of HCC in mice. Conclusion: These findings provide more insights into the immunomodulatory roles of HSCs in HCC progression and indicate that modulation of the C3 pathway might be a novel therapeutic approach for liver cancer.

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Section: Discussionmentioning

confidence: 50%

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

Huang

et al. 2020

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“…CD46 deficiency is accompanied hence by recurrent infections throughout life and patients with serum C3 deficiency have recurrent infections early in life. Of note, whilst C3 deficiency was long thought to be based solely on reduced pathogen lytic activity and impairment of innate immunity, it is now understood that C3-deficiency indeed also impairs adaptive immunity ( 21 ). Increased CTSL-mediated C3 activation, on the other hand, drives Th1 hyper-activity in rheumatoid arthritis and in systemic lupus erythematosus ( 5 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

Asparaginyl Endopeptidase (Legumain) Supports Human Th1 Induction via Cathepsin L-Mediated Intracellular C3 Activation

et al. 2018

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Autocrine activation of the complement receptors C3aR and CD46 by complement activation components C3a and C3b produced through C3 cleavage by the protease cathepsin L (CTSL) during T cell stimulation is a requirement for IFN-γ production and Th1 induction in human CD4+ T cells. Thus, lack of autocrine CD46 activation, such as in CD46-deficient patients, is associated with defective Th1 responses and recurrent infections. We have identified LGMN [the gene coding for legumain, also known as asparaginyl endopeptidase (AEP)] as one of the key genes induced by CD46 co-stimulation during human CD4+ T cell activation. AEP processes and activates a range of proteins, among those α1-thymosin and CTSL, which both drive intrinsically Th1 activity—but has so far not been described to be functionally active in human T cells. Here we found that pharmacological inhibition of AEP during activation of human CD4+ T cells reduced CTSL activation and the CTSL-mediated generation of intracellular C3a. This translated into a specific reduction of IFN-γ production without affecting cell proliferation or survival. In line with these findings, CD4+ T cells isolated from Lgmn−/− mice also displayed a specific defect in IFN-γ secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine α1-thymosin activation in T cell-derived IFN-γ production. These data suggest that AEP is an “upstream” activator of the CTSL-C3-IFN-γ axis in human CD4+ T cells and hence an important supporter of human Th1 induction.

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“…Several studies have gone on to describe the direct and indirect involvement of the complement system in modulating B-cell responses, albeit not as a consequence of trauma. For example, C3 is required for memory B-cell differentiation and locally generated C5a by peritoneal macrophages is required for chemokine ligand 13 synthesis which is further needed for B1-cell homeostasis ( 168 , 169 ). Activation of the BCR increased the amount of intracellular C3aR though it could not be detected on the cell surface even after activation.…”

Section: Future Perspectivesmentioning

confidence: 99%

Complement After Trauma: Suturing Innate and Adaptive Immunity

2018

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The overpowering effect of trauma on the immune system is undisputed. Severe trauma is characterized by systemic cytokine generation, activation and dysregulation of systemic inflammatory response complementopathy and coagulopathy, has been immensely instrumental in understanding the underlying mechanisms of the innate immune system during systemic inflammation. The compartmentalized functions of the innate and adaptive immune systems are being gradually recognized as an overlapping, interactive and dynamic system of responsive elements. Nonetheless the current knowledge of the complement cascade and its interaction with adaptive immune response mediators and cells, including T- and B-cells, is limited. In this review, we discuss what is known about the bridging effects of the complement system on the adaptive immune system and which unexplored areas could be crucial in understanding how the complement and adaptive immune systems interact following trauma.

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Human plasma C3 is essential for the development of memory B, but not T, lymphocytes

Cited by 21 publications

References 25 publications

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

<p>Activated Hepatic Stellate Cells (HSCs) Exert Immunosuppressive Effects in Hepatocellular Carcinoma by Producing Complement C3</p>

Asparaginyl Endopeptidase (Legumain) Supports Human Th1 Induction via Cathepsin L-Mediated Intracellular C3 Activation

Complement After Trauma: Suturing Innate and Adaptive Immunity

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