Beta-1,3 Oligoglucans Specifically Bind to Immune Receptor CD28 and May Enhance T Cell Activation

Abstract

Beta glucans are known to have immunomodulatory effects that mediated by a variety of mechanisms. In this article, we describe experiments and simulations suggesting that beta-1,3 glucans may promote activation of T cells by a previously unknown mechanism. First, we find that treatment of a T lymphoblast cell line with beta-1,3 oligoglucan significantly increases mRNA levels of T cell activation-associated cytokines, especially in the presence of the agonistic anti-CD3 antibody. This immunostimulatory activity was observed in the absence of dectin-1, a known receptor for beta-1,3 glucans. To clarify the molecular mechanism underlying this activity, we performed a series of molecular dynamics simulations and free-energy calculations to explore the interaction of beta-1,3 oligoglucans with potential immune receptors. While the simulations reveal little association between beta-1,3 oligoglucan and the immune receptor CD3, we find that beta-1,3 oligoglucans bind to CD28 near the region identified as the binding site for its natural ligands CD80 and CD86. Using a rigorous absolute binding free-energy technique, we calculate a dissociation constant in the low millimolar range for binding of 8-mer beta-1,3 oligoglucan to this site on CD28. The simulations show this binding to be specific, as no such association is computed for alpha-1,4 oligoglucan. This study suggests that beta-1,3 glucans bind to CD28 and may stimulate T cell activation collaboratively with T cell receptor activation, thereby stimulating immune function.

The Effect of Novel Selenopolysaccharide Isolated from Lentinula edodes Mycelium on Human T Lymphocytes Activation, Proliferation, and Cytokines Synthesis

“…Interestingly, recent research has shown that β-glucans may stimulate an immune response by binding to CD28 on the surface of T cells and that this stimulation is potentiated by CD3 activation. Cormer and colleagues explored interactions of β-1,3 glucans with the CD28 receptor and found that glucan molecules insert themselves into a channel on the surface of CD28 and moreover diffuse around the receptor, coming into contact with different regions of the protein [ 62 ]. This is another potential mechanism underlying the observed immunomodulatory effects of Se-Le-30.…”

Glucans, Paramylon and Other Algae Bioactive Molecules

“…The properties and benefits of algal compounds with nutraceutical, pharmacological, and biomedical interest [ 2 , 3 ] are the main topics of this Special Issue in International Journal of Molecular Sciences , with major emphasis on polysaccharides, of which are the most exploited compounds worldwide. This main topic is expanded to include polysaccharides of other origins, such as fungi [ 4 , 5 ], which also possess biological activity, and review the defense mechanisms triggered by the interaction of these compounds with organisms, which are at the base of immunity [ 6 ].…”

“…Comer et al [ 3 ] tested two 5-mer oligoglucans (β-1,3 laminaripentaose, and α-1,4 maltopentaose) for their capacity to induce cytokine expression. They verified an immune-stimulant effect of β-1,3 oligoglucans on T lymphocytes, with a significant increase in the mRNA levels of T-cell-activation-associated cytokines, especially in the presence of the agonistic anti-CD3 antibody and the absence of dectin-1.…”