Deciphering the molecular basis of mycobacteria and lipoglycan recognition by the C-type lectin Dectin-2

<jats:title>Abstract</jats:title><jats:p>Dectin-2 is a C-type lectin involved in the recognition of several pathogens such as <jats:italic>Aspergillus fumigatus</jats:italic>, <jats:italic>Candida albicans</jats:italic>, <jats:italic>Schistosoma mansonii</jats:italic>, and <jats:italic>Mycobacterium tuberculosis</jats:italic> that triggers Th17 immune responses. Identifying pathogen ligands and understanding the molecular basis of their recognition is one of the current challenges. Purified <jats:italic>M</jats:italic>. <jats:italic>tuberculosis</jats:italic> mannose-capped lipoarabinomannan (ManLAM) was shown to induce signaling <jats:italic>via</jats:italic> Dectin-2, an activity that requires the (α1 → 2)-linked mannosides forming the caps. Here, using isogenic <jats:italic>M</jats:italic>. <jats:italic>tuberculosis</jats:italic> mutant strains, we demonstrate that ManLAM is a <jats:italic>bona fide</jats:italic> and actually the sole ligand mediating bacilli recognition by Dectin-2, although <jats:italic>M</jats:italic>. <jats:italic>tuberculosis</jats:italic> produces a variety of cell envelope mannoconjugates, such as phosphatidyl-<jats:italic>myo</jats:italic>-inositol hexamannosides, lipomannan or manno(lipo)proteins, that bear (α1 → 2)-linked mannosides. In addition, we found that Dectin-2 can recognize lipoglycans from other bacterial species, such as <jats:italic>Saccharotrix aerocolonigenes</jats:italic> or the human opportunistic pathogen <jats:italic>Tsukamurella paurometabola</jats:italic>, suggesting that lipoglycans are prototypical Dectin-2 ligands. Finally, from a structure/function relationship perspective, we show, using lipoglycan variants and synthetic mannodendrimers, that dimannoside caps and multivalent interaction are required for ligand binding to and signaling <jats:italic>via</jats:italic> Dectin-2. Better understanding of the molecular basis of ligand recognition by Dectin-2 will pave the way for the rational design of potent adjuvants targeting this receptor.</jats:p>