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*
Evans Memorial Department of Clinical Research and Departments of Medicine and Microbiology, Boston University School of Medicine, Boston, MA 02118; and
Veterans Affairs Medical Center and Departments of Medicine and Microbiology, University of Iowa, Iowa City, IA 52242
Cryptococcosis is a leading cause of death among individuals with
compromised T cell function. Soluble Cryptococcus
neoformans mannoproteins (MP) have emerged as promising vaccine
candidates due to their capacity to elicit delayed-type
hypersensitivity and Th type 1-like cytokines, both critical to the
clearance of this pathogenic yeast. In this study, the mechanisms
responsible for the potent immunostimulatory properties of MP were
explored. Using Chinese hamster ovary cells expressing human macrophage
mannose receptor (MMR), we determined that MP is a MMR ligand.
Functionally, competitive blockade of multilectin mannose receptors
(MR) on APCs diminished MP-dependent stimulation of primary T cells
from immunized mice and the MP-reactive CD4+ T cell
hybridoma, P1D6, by 72 and 99%, respectively. Removal of
O-linked saccharides from MP by 
-elimination
inhibited MP-dependent stimulation of P1D6 and primary T cells by 89
and 90%, respectively. In addition, MP-dependent stimulation of P1D6
was abrogated after digestion with proteinase K, suggesting the protein
core of MP contributed the antigenic moiety presented by APC.
Stimulation of P1D6 by MP also was abolished using APC obtained from
invariant chain-deficient mice, demonstrating Ag presentation was MHC
class II restricted. Our data suggest that MP is a ligand for the MMR
and that T cell stimulation is functionally inhibited either by
competitive blockade of MR or by removal of carbohydrate residues
critical for recognition. The demonstration that efficient T cell
responses to MP require recognition of terminal mannose groups by MMR
provides both a molecular basis for the immunogenicity of cryptococcal
MP and support for vaccination strategies that target
MR.
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