CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

Abstract

Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4 + and CD8 + T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined. Here, we show that activation of either T cell subset in a mouse model of CGD is contingent upon the nature of the fungal vaccine, the involvement of distinct innate receptor signaling pathways, and the mode of antigen routing and presentation in DCs. Aspergillus conidia activated CD8 + T cells upon sorting to the Rab14 + endosomal compartment required for alternative MHC class I presentation. Cross-priming of CD8 + T cells failed to occur in mice with CGD due to defective DC endosomal alkalinization and autophagy. However, long-lasting antifungal protection and disease control were successfully achieved upon vaccination with purified fungal antigens that activated CD4 + T cells through the endosome/lysosome pathway. Our study thus indicates that distinct intracellular pathways are exploited for the priming of CD4 + and CD8 + T cells to A. fumigatus and suggests that CD4 + T cell vaccination may be able to overcome defective antifungal CD8 + T cell memory in individuals with CGD.

Intersection of autophagy with pathways of antigen presentation

“…The authors propose a direct role for the autophagosome itself as a compartment for cross-presentation (Li et al, 2011a). The notion that autophagy facilitates cross-presentation is supported by the observation that the autophagy machinery promotes the transit of Aspergillus conidia associated antigen from the early endosome to a Rab14+ cross-presenting compartment (De Luca et al, 2012). Therefore, the role of autophagy in cross-presentation remains to be further explored in detail.…”

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

“…Indeed, the very notion that autophagy partakes in cross-presentation is controversial. While it has been suggested by some studies to play a role, [8][9][10] others have concluded that cross-presentation is autophagy-independent. 11 Resolving this is important given the therapeutic potential of targeting cross-presentation with drugs that manipulate autophagy.…”

NADPH oxidase regulates efficacy of vaccination in aspergillosis

“…Recognition of conidia by CD8 + T cells required TLR3 and TIR domain-containing adapter-inducing interferon-b (TRIF). On the other hand, MyD88 and TLR6 were necessary for the action of one of the soluble antigens, and other soluble antigens had distinct TLR requirements for driving CD4 + T cell activation (13). This work highlights the complexity of antigen recognition at the level of PRRs.…”

“…They found that in wildtype mice, CD8 + T cells are essential for protection upon vaccination with conidia, whereas immunization with soluble Aspergillus proteins admixed with CpG confers protection in a CD4 + T cell-dependent manner (13). The finding that CD8 + T cells are the mediators of protection following immunization with conidia is somewhat surprising in light of previous work reporting that exposure to these fungal elements in primary infection induces a pronounced CD4 + T cell differentiation (4).…”

“…An alternative pathway is that antigens "leak" or escape from the phagosome and enter the cytosol in the absence of fusion of phagosome/endoplasmic reticulum; the antigens in the cytosol are digested by the proteasome, bind to MHC I, and traffic to the cell surface. In this issue of the JCI, De Luca et al (13) provide vital new information regarding the contribution of CD4 + and CD8 + T cells in host defenses against this devastating fungal pathogen. In this creative work, they use the p47 phox-/-model of CGD, in which the mice have defective NADPH oxidase, to decipher the antigen-presenting pathways in DCs that prompt CD4 + and CD8 + T cell activation.…”