Structural differences in lipomannans from pathogenic and nonpathogenic mycobacteria that impact CD1b-restricted T cell responses

Mannosylated molecules on the Mycobacterium tuberculosis surface are important determinants in the immunopathogenesis of tuberculosis. To date, much attention has been paid to mannose-capped lipoarabinomannan, which mediates phagocytosis and intracellular trafficking of M. tuberculosis by engaging the macrophage mannose receptor and subsequently binds to intracellular CD1b molecules for presentation to T cells. Another important mannosylated lipoglycan on the M. tuberculosis surface is lipomannan (LM). Comparative structural detail of the LMs from virulent and avirulent strains is limited as is knowledge regarding their differential capacity to be recognized by the adaptive immune response. Here, we purified LM from the avirulent M. smegmatis and the virulent M. tuberculosis H(37)R(v), performed a comparative structural biochemical analysis, and addressed their ability to stimulate CD1b-restricted T cell clones. We found that M. tuberculosis H(37)R(v) produces a large neutral LM (TB-LM); in contrast, M. smegmatis produces a smaller linear acidic LM (SmegLM) with a high succinate content. Correspondingly, TB-LM was not as efficiently presented to CD1b-restricted T cells as SmegLM. Thus, here we correlate the structure-function relationships for LMs with CD1b-restricted T cell responses and provide evidence that the structural features of TB-LM contribute to its diminished T cell responsiveness.