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Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390
Hyaluronan (HA) is a large glycosaminoglycan consisting of
repeating disaccharide units of glucuronic acid and
N-acetylglucosamine. HA is known to act as a filling
material of extracellular matrices and as an adhesive substrate for
cellular migration. Here we report that dendritic cells (DC) express
mRNAs for HA synthases and hyaluronidases, actively synthesize HA, and
display HA on their surfaces. Interestingly, HA expression levels on DC
were not significantly altered by their maturation states. With respect
to physiological function, three specific HA inhibitors, i.e., bovine
proteoglycan, a 12-mer HA-binding peptide (GAHWQFNALTVR) termed
Pep-1, and an oligomeric Pep-1 formulation, all interfered with
DC-induced activation of CD4+ T cells isolated from DO11.10
TCR transgenic mice. For example, Pep-1 oligomer efficiently inhibited
DC-dependent cluster formation, IL-2 and IFN-
production, and
proliferation by DO11.10 T cells in vitro without affecting the
viabilities of DC or T cells, DC function to uptake exogenous proteins,
or DC-T cell conjugate formation at earlier time points. These
observations suggest a paracrine mechanism by which DC-associated HA
facilitates some of the late changes in T cell activation. Although T
cells constitutively expressed mRNAs for HA synthases and
hyaluronidases, their surface HA expression became detectable only
after activation. Oligomeric Pep-1 and bovine proteoglycan both
inhibited mitogen-triggered T cell activation in the absence of DC,
suggesting an autocrine mechanism by which HA expressed by T cells
assists their own activation processes. Finally, adoptively transferred
DO11.10 T cells showed progressive mitosis when stimulated with
Ag-pulsed DC in living animals, and this clonal expansion was inhibited
significantly by administration of Pep-1 oligomer. Our findings may
introduce a new concept that relatively simple carbohydrate moieties
expressed on DC and perhaps T cells play an important immunomodulatory
role during Ag presentation.
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