Abstract
Natural killer T (NKT) cells exhibit a specific tissue distribution, displaying the liver the highest NKT/conventional T cell ratio. Upon antigen stimulation, NKT cells secrete Th1 cytokines, including interferon γ (IFNγ), and Th2 cytokines, including IL-4 that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver. Cysteine cathepsins control hepatic inflammation by regulating κB-dependent gene expression. However, the contribution of cysteine cathepsins other than Cathepsin S to NKT cell activation has remained largely unexplored. Here we report that cysteine cathepsins, cathepsin B (CTSB) and cathepsin S (CTSS), regulate different aspects of NKT cell activation. Inhibition of CTSB or CTSS reduced hepatic NKT cell expansion in a mouse model after LPS challenge. By contrast, only CTSS inhibition reduced IFNγ and IL-4 secretion after in vivo α-GalCer administration. Accordingly, in vitro studies reveal that only CTSS was able to control α-GalCer-dependent loading in antigen-presenting cells (APCs), probably due to altered endolysosomal protein degradation. In summary, our study discloses the participation of cysteine cathepsins, CTSB and CTSS, in the activation of NKT cells in vivo and in vitro.
Highlights
Recent studies indicate that cysteine cathepsins serve as regulatory enzymes, acting beyond simple housekeeping proteases, that harbor important functions outside the lysosome [1]
Given the importance of LPS as a central player in inducing inflammation in multiple liver diseases, we evaluated if iNKT cell activation in response to LPS is influenced by cysteine cathepsins
The Cathepsin B (CTSB) inhibitor blocked this iNKT cell increase, and interestingly, the Cathepsin S (CTSS) inhibitor blocked the increase, but caused a decrease in the frequency of the iNKT cell population to approximately 7% (Figure 1A). These results indicate that CTSB and CTSS influence the extent of iNKT cell activation leading to a decrease in this population
Summary
Recent studies indicate that cysteine cathepsins serve as regulatory enzymes, acting beyond simple housekeeping proteases, that harbor important functions outside the lysosome [1]. We have recently revealed the participation of cysteine cathepsins [Cathepsin B (CTSB) and Cathepsin S (CTSS)] in controlling hepatic NF-κB-dependent inflammation via sirtuin-1 regulation [3], and the role of CTSB in promoting hepatic stellate cell (HSC) activation and liver fibrosis [4]. Cysteine cathepsins have been implicated in antigen presentation, being CTSS the protease most highly expressed in professional antigenpresenting cells (APCs) [5, 6]. Natural killer T (NKT) cells are unconventional T cells that express both T cell receptors (TCRs) and natural killer (NK) cell receptors. Based on TCR expression, NKT cells can be divided into classical NKT cells, known as type I or invariant NKT cells (iNKT cells) and non-classical
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