Differential Lysosomal Proteolysis in Antigen-Presenting Cells Determines Antigen Fate

Abstract

Antigen-presenting cells (APCs) internalize antigens and present antigen-derived peptides to T cells. Although APCs have been thought to exhibit a well-developed capacity for lysosomal proteolysis, here we found that they can exhibit two distinct strategies upon antigen encounter. Whereas macrophages contained high levels of lysosomal proteases and rapidly degraded internalized proteins, dendritic cells (DCs) and B lymphocytes were protease-poor, resulting in a limited capacity for lysosomal degradation. Consistent with these findings, DCs in vivo degraded internalized antigens slowly and thus retained antigen in lymphoid organs for extended periods. Limited lysosomal proteolysis also favored antigen presentation. These results help explain why DCs are able to efficiently accumulate, process, and disseminate antigens and microbes systemically for purposes of tolerance and immunity.

Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice

“…[4][5][6][7] Post AC engulfment, macrophages appear to be capable of fully digesting AC-associated antigens and limit their access to antigen presentation compartments, and therefore are inefficient at T-cell priming. 8 In contrast, DC are highly efficient at processing and presentation of engulfed antigens, using either direct or cross-presentation pathways, which either anergizes or activates potentially self-reactive T cells, depending on the context of antigen presentation. [9][10][11] Under homeostatic conditions, anti-inflammatory cytokines and natural regulatory T cells channel DC self-antigen presentation to induce regulatory T-cell differentiation from naïve CD4 T-cell precursors, and to tolerize effector CD8 T cells.…”

Diverse regulatory roles for lysosomal proteases in the immune response

“…Importantly, several recent studies highlight the fact that lysosomal proteases can destroy as well as generate T-cell epitopes. DC express reduced levels of lysosomal enzymes compared with macrophages, which appear to improve rather than hinder their performance as APC [37]. They can also attenuate protease activity, at least in newly formed phagosomes, by raising phagosomal pH, which protected antigen for subsequent cross-presentation on class I MHC molecules [38].…”

Design of cell-permeable, fluorescent activity-based probes for the lysosomal cysteine protease asparaginyl endopeptidase (AEP)/legumain

“…3a). Although both probes are highly specific for legumain in B cell lysates, recent studies have suggested that B cells contain lower levels of lysosomal protease activity than other antigen presenting cells [15]. We therefore decided to assess the potency and specificity of our ABPs in the murine monocytic cell line RAW264.7 (Fig 3b).…”