Cystatin C Regulates MHC-? Expression And Erk-dependent Polarizing Cytokine Secretion In Dendritic Cells

Cystatin C is a predominantly expressed cysteine protease inhibitor to protect cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases from parasites.Although it is commonly used as a bio-marker for evaluating renal functions due to its relatively small molecular weight,recent studies have shown that Cystatin C is also associated with the immunological disorders in various pathophysiological conditions.How does Cystatin C affect the immune system cells,especially antigen presenting cells(APCs)dendritic cells(DC),the initiator of host immunity,however,is far from clear.In this study,Cystatin C overexpression DC clone--DC2.4 was used as the research object to explore the influence of Cystatin C on various functions of dendritic cells.We found that genetic over-expression of Cystatin C in DC2.4 increased their phagocytosis of foreign antigens but reduced their capacity to stimulate T cell proliferation.Furthermore,we found that the compromised T stimulating potential of the Cystatin C-overexpression DC2.4 was co-related with their reduced MHC-II processing due to diminished contents of H2 DM,a key chaperon for MHC-II maturation.On the other hand,under the influence of Cystatin C,the DC tended to skew T cells towards inflammatory Th1/Th17 rather than anti-inflammatory Th2 differentiation,which was underpinned by their Erk/MAP kinase dependent secretion of polarizing cytokines.Collectively,the alteration of DC functions by Cystatin C and its mechanisms found in this study could not only explain how this protease inhibitor could play regulatory roles in the host immune responses reported in literatures,but also open up a revenue for the development of Cystatin C derivatives for the treatment of inflammation or autoimmune-related diseases.