The polysaccharide capsule of Cryptococcus neoformans interferes with human dendritic cell maturation and activation

Abstract

The ability of encapsulated and acapsular strains of Cryptococcus neoformans to activate dendritic cells (DC) derived from monocytes stimulated with granulocyte macrophage-colony stimulating factor and interleukin-4 was evaluated. Profound differences in DC response to encapsulated and acapsular C. neoformans strains were observed. In particular, (i) the acapsular strain was easily phagocytosed by immature DC, and the process induced several molecular markers, such as major histocompatibility complex (MHC) class I and class II, CD40, and CD83, which are characteristic of mature DC; (ii) the encapsulated strain did not up-regulate MHC class I and class II and CD83 molecules; (iii) the soluble capsular polysaccharide glucuronoxylomannan (GXM) is unable to regulate MHC class I and class II molecules; (iv) the addition of monoclonal antibody to GXM (anti-GXM) to the encapsulated strain facilitated antigen-presenting cell maturation by promoting ingestion of C. neoformans via Fc receptor for immunoglobulin G (FcgammaR)II (CD32) and FcgammaRIII (CD16); (v) pertubation of FcRgammaII or FcgammaRIII was insufficient to promote DC maturation; and (vi) optimal DC maturation permitted efficient T cell activation and differentiation, as documented by the enhancement of lymphoproliferation and interferon-gamma production. These results indicate that the C. neoformans capsule interferes with DC activation and maturation, indicating a new pathway by which the fungus may avoid an efficient T cell response.

Dendritic Cell-Based Immunization Ameliorates Pulmonary Infection with Highly Virulent Cryptococcus gattii

“…They also showed that TNF-␣ could restore DC maturation to induce T cell responses in the presence of C. gattii, which suggested the potential of DC-based therapies to improve the outcomes of patients with C. gattii infections. Another study showed that encapsulated C. neoformans strain B3501 (serotype D) could induce human DC maturation based on DC expression of CD40, CD86, and MHC-II (28). In our study, murine BMDCs did not mature in the presence of encapsulated C. gattii strains, because they did not efficiently engulf encapsulated C. gattii strains (Fig.…”

Role of Capsule and Interleukin-6 in Long-Term Immune Control ofCryptococcus neoformansInfection by Specifically Activated Human Peripheral Blood Mononuclear Cells

“…Macrophages and dendritic cells have been shown to bind and phagocytose acapsular, but not encapsulated, C. neoformans via macrophage mannose receptors (9,19,21,31), engagement of which, at least in some settings, has been linked to IL-6 production (35). Acapsular organisms and cryptococcal mannoprotein have been shown to induce dendritic cell maturation and activation (27,34), and mannoprotein has been shown to interact with multiple mannose receptors (24).…”

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

“…GXM has profound effects on both innate and adaptive immune mechanisms. GXM can reduce MHC class II expression on APC (1, 2), inhibit activation and maturation of dendritic cells (3), reduce T cell proliferation in the presence of APC (4,5), dampen Th1 response (5,6), induce apoptosis of T cells in the presence of monocytes/macrophages via the Fas ligand/ Fas system (7), inhibit the production of proinflammatory cytokines by monocytes (8), and induce IL-10 production by monocytes (9,10).…”

“…The mononuclear cells were separated by density gradient centrifugation on FicollHypaque (13). Macrophages and dendritic cells were obtained as described previously (3,30).…”