The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

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Abstract
A 2‐kDa synthetic derivative of the macrophage‐activating lipopeptide (MALP‐2) from Mycoplasma fermentans is a potent inducer of monocytes/macrophages and improves the immunogenicity of antigens co‐administered by systemic and mucosal routes. Dendritic cells (DC) are the most potent antigen‐presenting cells, which are able to prime naive T cells in vivo. To elucidate the underlying mechanisms of MALP‐2 adjuvanticity, we analyzed its activity on bone marrow‐derived murine DC. In vitro stimulation of immature murine DC with MALP‐2 resulted in the induction of maturation with up‐regulated expression of MHC class II, costimulatory (CD80, CD86) and adhesion (CD40, CD54) molecules. MALP‐2 also enhances the secretion of cytokines (IL‐1α, IL‐6 and IL‐12), and increases DC stimulatory activity on naive and antigen‐specific T cells. Further studies demonstrated that MALP‐2 treatment of DC results in a dose‐dependent shift from the protein pattern of proteasomes to immunoproteasomes (up‐regulation of LMP2, LMP7 and MECL1), which correlates with an increased proteolytic activity. Thus, the adjuvanticity of MALP‐2 can be mediated, at least in part, by the stimulation of DC maturation, which in turn leads to an improved antigen presentation. Therefore, MALP‐2 is a promising molecule for the development of immune therapeutic or prophylactic interventions.

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