Adaptive Immunity to Cryptococcus neoformans Infections

Abstract

The Cryptococcus neoformans/Cryptococcus gattii species complex is a group of fungal pathogens with different phenotypic and genotypic diversity that cause disease in immunocompromised patients as well as in healthy individuals. The immune response resulting from the interaction between Cryptococcus and the host immune system is a key determinant of the disease outcome. The species C. neoformans causes the majority of human infections, and therefore almost all immunological studies focused on C. neoformans infections. Thus, this review presents current understanding on the role of adaptive immunity during C. neoformans infections both in humans and in animal models of disease.

Keywords: CD4; Cryptococcus; adaptive immunity; cytokines; dendritic cells; helper T cell type 1 (Th1); helper T cell type 17 (Th17); helper T cell type 2 (Th2); immune reconstitution inflammatory syndrome (IRIS).

Figure 1

Adaptive immunity during Cryptococcus infection. Current understanding of initiation, development and function of adaptive immunity during C. neoformans infection in the mouse model (A) or in humans (B). (1) C. neoformans pathogen-associated molecule patterns (PAMPS) are recognized by innate immune cells (macrophages and DCs). This recognition triggers phagocytosis, antigen processing and presentation of C. neoformans antigens to naïve T cells by antigen presenting cells. (2) Antigen presentation induces activation and differentiation of naïve T cells into Th1, Th2, Tregs and Th17 cells. (3) The presence of IFNγ and IL-12 promotes Th1 differentiation, while the presence of IL-4, as well as expression of costimulatory molecules CD86 and OX40L induces Th2 differentiation. IL-23 induces Th17 differentiation in the absence of IFNγ and IL-4. (4) Th1 cells promote cryptococcal killing either by direct contact, or by producing the Th1 cytokines IFNγ, IL-12 and IL-2 that stimulate phagocyte recruitment and polarization to classically activated macrophages that eliminate C. neoformans cells. In contrast, Th2 immune responses mediated by IL-4, IL-5 and IL-13 result in increased eosinophilia and polarization of alternatively activated macrophages, and ultimately lead to the dissemination of C. neoformans cells and disease exacerbation. These Th2 immune responses can be blocked by the action of Tregs. In the absence of Th cells, IL-17 production intensifies cryptococcal disease through neutrophilia. Green arrows denote beneficial immune responses, whereas red arrows denote detrimental immune responses. CM (Cryptococcus meningitis), DCs (dendritic cells), IFNγ (interferon gamma), IL- (interleukin, IL-12: interleukin-12), IRF4 (IFN regulatory factor 4), IRIS (immune reconstitution inflammatory syndrome), Th (helper T cell), Tregs (regulatory T cells), Ø (macrophage), M1Ø (classically activated macrophage), M2Ø (alternatively activated macrophage), CD4 (helper T cell), CD8 (cytotoxic T cell), CD86 (costimulatory molecule 86), OX40L (costimulatory molecule OX40L, ligand of OX40 receptor on T cells).

Figure 1

Adaptive immunity during Cryptococcus infection. Current understanding of initiation, development and function of adaptive immunity during C. neoformans infection in the mouse model (A) or in humans (B). (1) C. neoformans pathogen-associated molecule patterns (PAMPS) are recognized by innate immune cells (macrophages and DCs). This recognition triggers phagocytosis, antigen processing and presentation of C. neoformans antigens to naïve T cells by antigen presenting cells. (2) Antigen presentation induces activation and differentiation of naïve T cells into Th1, Th2, Tregs and Th17 cells. (3) The presence of IFNγ and IL-12 promotes Th1 differentiation, while the presence of IL-4, as well as expression of costimulatory molecules CD86 and OX40L induces Th2 differentiation. IL-23 induces Th17 differentiation in the absence of IFNγ and IL-4. (4) Th1 cells promote cryptococcal killing either by direct contact, or by producing the Th1 cytokines IFNγ, IL-12 and IL-2 that stimulate phagocyte recruitment and polarization to classically activated macrophages that eliminate C. neoformans cells. In contrast, Th2 immune responses mediated by IL-4, IL-5 and IL-13 result in increased eosinophilia and polarization of alternatively activated macrophages, and ultimately lead to the dissemination of C. neoformans cells and disease exacerbation. These Th2 immune responses can be blocked by the action of Tregs. In the absence of Th cells, IL-17 production intensifies cryptococcal disease through neutrophilia. Green arrows denote beneficial immune responses, whereas red arrows denote detrimental immune responses. CM (Cryptococcus meningitis), DCs (dendritic cells), IFNγ (interferon gamma), IL- (interleukin, IL-12: interleukin-12), IRF4 (IFN regulatory factor 4), IRIS (immune reconstitution inflammatory syndrome), Th (helper T cell), Tregs (regulatory T cells), Ø (macrophage), M1Ø (classically activated macrophage), M2Ø (alternatively activated macrophage), CD4 (helper T cell), CD8 (cytotoxic T cell), CD86 (costimulatory molecule 86), OX40L (costimulatory molecule OX40L, ligand of OX40 receptor on T cells).