Marta Feldmesser¹ and Arturo Casadevall^1,2

1Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology², Albert Einstein College of Medicine, Golding Building Room 701, 1300 Morris Park Ave., Bronx, NY 10461

Received 1/5/98 Accepted 1/9/98

4. THE POLYSACCHARIDE CAPSULE

4.1 Immunomodulatory effects

The polysaccharide capsule of C. neoformans is required for virulence (23), and is composed predominantly of glucuronoxylomannan (GXM). Other constituents include galactoxylomannan and mannoprotein, which together comprise 12% of the capsule by mass (24). GXM is the major immunodominant antigen (Ag) of encapsulated strains and is the target recognized by most mAbs developed to date. GXM has immunosuppressant effects on multiple arms of the immune response (figure 1). GXM blocks binding of IgG found in normal human serum to the cryptococcal cell wall. Because this Ab binding is required for maximal rates of attachment to macrophages and for macrophage ingestion of yeast (25), phagocytosis is reduced. Phagocytosis is inhibited by the addition of capsular polysaccharide to acapsular strains in vitro (21). Complement activation differs between capsulated and acapsular strain. For unencapsulated C. neoformans, classical pathway complement initiation occurs, while for encapsulated strains, complement activation is limited to the alternative pathway (26). The polysaccharide blocks antigenic sites on the cryptococcal cell wall that are responsible for binding of C3 (27). C. neoformans capsular polysaccharide (CNPS) also inhibits C5-dependent leukocyte migration (28), blocks IL-8-induced neutrophil chemotaxis (29) and induces shedding of L-selectin by neutrophils, which may in part be responsible for the reduced cellular infiltration into infected tissues of patients with disseminated cryptococcosis (30). GXM also induces a T suppressor cell to secrete a T-suppressor factor via an Ag-presenting cell (31). Cryptococcal culture filtrate antigens induce a T suppressor cascade that results in the suppression of DTH (32,33). CNPS suppresses lymphocyte proliferation in vitro (34), and blocks the upregulation of B7-1 expression that occurs in response to coincubation of peripheral blood mononuclear cells (PBMCs) with C. neoformans (35). Further, CNPS enhances infectivity of PBMCs for HIV-1 in vitro (36) and increases production of p24 Ag after infection of H9 cells with HIV-1-infected H9 cells (37). In mice, injection of CNPS reduces Ab production following challenge immunization with polysaccharide emulsified in Freund’s incomplete adjuvant (38). Thus, the cryptococcal capsule downregulates multiple arms of the host immune response in that it is antiphagocytic, prevents the initiation of the classical complement pathway, blocks inflammatory cell recruitment, diminishes Ag presentation in response to infection, suppresses the development of DTH and may reduce Ab production in response to infection. Further, in patients with AIDS, cryptococcal polysaccharide may enhance HIV replication.

Figure 1. Summary of immunomodulatory effects of cryptococcal capsular polysaccharide.

4.2 Antigenic characteristics of cryptococcal capsular polysaccharide

Cryptococcal polysaccharide is classified as a T independent Ag because it induces a humoral response in the absence of T cell help and does not induce B cell memory or isotype class switching in secondary immune responses (39). The inability of GXM to induce humoral responses in CBA/cHN xid mice and ability to recruit regulatory T cells that both suppress and amplify the specific B cell response further classify it as a Type 2 T independent Ag (40). Cryptococcal strains have been classified into four serotypes on the basis of reciprocal agglutinin absorptions from rabbits immunized with a variety of strains of C. neoformans (41-43). By antigenic analysis of the four serotypes by slide agglutination with reciprocal adsorption methods, Ikeda demonstrated the presence of eight antigenic determinants (44).