Cystatin C regulates major histocompatibility complex‐II–peptide presentation and extracellular signal‐regulated kinase‐dependent polarizing cytokine production by bone marrow‐derived dendritic cells

Abstract

Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow‐derived DCs (BMDCs) reduced their capacity to stimulate CD4+ T‐cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex‐II presentation owing to diminished levels of the chaperon H2‐DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T‐helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal‐regulated kinase 1/2 mitogen‐activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C‐related immunological diseases.

Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV

“…CstC, as a cathepsin S inhibitor and regulator, plays a pivotal role in the control of cleavage and removal of the MHC class II invariant chain (Ii) ( 29 , 50 ). It also downregulates the MHC-II chaperon H2-DM, resulting in diminished MHC-II–peptide presentation and reduced T-cell proliferation ( 64 ). CstC and cathepsin S have been shown to contribute to MHC class II antigen processing and presentation ( 11 , 64 ).…”

“…It also downregulates the MHC-II chaperon H2-DM, resulting in diminished MHC-II–peptide presentation and reduced T-cell proliferation ( 64 ). CstC and cathepsin S have been shown to contribute to MHC class II antigen processing and presentation ( 11 , 64 ). Here, we demonstrated that the silencing of CstC induces a significant increased expression of HLA class II at the cell surface during Mtb infection and coinfection with HIV, but not during HIV mono-infection.…”

Secreted cystatins decrease proliferation and enhance apoptosis of human leukemic cells

“…[24]) more closely related to the promyelocytic (HL-60 and U937) or lymphocytic (Jurkat) cells used in the present study. Cystatin C is, for example, taken up by human macrophages [25], and externally added cystatin C has been reported to affect the viability of tuberculosis bacteria in infected macrophages [26] as well as the control of antigen presentation by dendritic cells [27][28][29]. Thus, there is ample evidence indicating that secreted cystatins could also have biological functions intracellularly, in many different cell types.…”

Self-Tolerance of Vascular Tissues Is Broken Down by Vascular Dendritic Cells in Response to Systemic Inflammation to Initiate Regional Autoinflammation

“…Phagocytic activity of vascular DCs was estimated by their uptake of soluble antigens followed by FACS analysis as described before ( 22 ). Briefly, C57BL/6 mice were injected i.v.…”