Mannoprotein fromCryptococcus neoformansPromotes T-Helper Type 1 Anticandidal Responses in Mice

Abstract

We previously demonstrated that mannoprotein (MP) from Cryptococcus neoformans (CnMP) stimulates interleukin-12 production by human monocytes, thus fostering a T-helper type 1 (Th1) protective anticryptococcal response. In this paper we show that CnMP was also able to induce a Candida albicans-directed protective Th1 response. This was demonstrated for mice immunized with CnMP by induction of a delayed-type hypersensitivity (DTH) reaction to C. albicans MP (CaMP) as well as induction of gamma interferon production by CD4؉ and CD8 ؉ splenic T cells stimulated in vitro with CaMP. CnMP-immunized mice were also partially protected from lethal systemic challenge with C. albicans, as shown by prolonged median survival times and decreased fungal burden in the kidney. Much evidence supports the validity of these cross-reactive and functional Th1 responses: (i) a non-cross-reactive C. albicans antigen, such as enolase, did not produce a DTH response to CaMP; (ii) passive adoptive transfer of T cells primed with CnMP induced a DTH reaction; (iii) C. neoformans extract elicited a DTH response to CaMP; and (iv) a monoclonal antibody (7H6) directed against a major and immunodominant T-cell-stimulatory 65-kDa MP (MP65) of C. albicans also recognized discrete 100-kDa constituents of C. neoformans extracts, as well as secretory constituents of the fungus. These results suggest the presence of common Th1 antigenic determinants in the mannoproteic material of C. neoformans and C. albicans epitopes, which should be considered in devising common strategies for immunoprophylactic or immunotherapeutic control of the fungi.

Mannoproteins fromCryptococcus neoformansPromote Dendritic Cell Maturation and Activation

“…DCs are able to secrete TNF-␣ and IL-12 when stimulated with MP1 and MP2; this activation involves IB␣ phosphorylation and degradation. IL-12 induction, but not TNF-␣ In a previous paper, we demonstrated that MPs from C. neoformans are able to induce a Th1-type response in vitro by using monocytes and T cells separated from peripheral blood mononuclear cells from healthy donors (36), and in subsequent papers, we demonstrated that immunization with MPs induced protective responses to C. neoformans and C. albicans challenge (33,35). DCs are critical in controlling early innate responses: they regulate long-lasting adaptive immunity and contribute to the maintenance of self-tolerance.…”

“…It possesses strong immunogenic properties, including induction of a T-cell response and partial protection against lethal infection (28). Recently we showed that CnMP induces cross-protection against systemic C. albicans challenge and that it is, at least in part, related to epitopes also common to CaMP (35). The protective T-cell response is governed by antigen-presenting cells, and dendritic cells (DCs) are the quintessential professional antigen-presenting cells.…”

“…It has been reported that various MPs from C. neoformans (6,23,27) share many biological effects; therefore, we were interested in testing the similarities or differences of two MPs isolated from culture supernatant of C. neoformans. Given that MPs are usually immunostimulating agents that favor protective T-cell responses (28,35) and that DCs have a key role in this process, the purpose of our study was to evaluate the effects of MP1 and MP2 on DC maturation and activation.…”

Cross-protective TH1 immunity against Aspergillus fumigatus and Candida albicans

“…The discovery of a defined peptide epitope activating T H 1 cells with cross-reactivity to the 2 most important fungal pathogens in humans is to our knowledge a novel finding and only little is known in mouse models. 37 The concept of heterologous immunity to different pathogens mediated by cross-reactive T cells has until now only been described in detail for viral infections, 38 for example, for influenza virus 39,40 and flavivirus. 41,42 The discovery of this mechanism has initiated the development of new vaccines that will target conserved protein domains of different flaviviral strains for induction of cross-protection.…”

A Yeast under Cover: the Capsule ofCryptococcus neoformans

“…These mannoproteins have been the focus of immunologic studies, as they appear to be involved in the induction of cell-mediated immunity (18,28,70,75,82) and cytokine production (48,81), both critical functions for clearing the fungus. Several of these proteins have been purified from acapsular strains of Cryptococcus by concanavalin A affinity (49,66), and one study suggests that they move through the cell wall and are released into the external environment (99).…”