Once committed, T cells express effector function largely, but not exclusively, through release of cytokines that allow the host to restrict growth of the fungus. Although several cytokines are pivotal in mediating protective immunity, IFN-γ
, and IL-17/22 are the three principal ones that contribute to protective immunity to several pathogenic fungi (183
) (). The action of the former two in fungal infections does not differ from that classically ascribed to them in other infectious diseases. They prompt release of nitric oxide and stimulate reactive oxygen intermediates, both of which are crucial cellular effectors. H. capsulatum
, however, survives the release of reactive oxygen intermediates (186
is also necessary for generation of optimal T cell–dependent immunity in murine cryptococcosis and histoplasmosis (187
). The absence of this cytokine is associated with depressed recruitment of T cells in cryptococcosis and defective T cell function in histoplasmosis. In both models, administration of TNF-α
-neutralizing antibody after infection is established does not affect the course of disease. These findings can be interpreted to mean that TNF-α
is necessary for the genesis of T cell immunity, but once T cells are operative, they do not require continued signaling from this cytokine.
Figure 4 Schematic illustration of the functional attributes of effector T cells in fungal infections. T helper (Th)1, Th2, Th17/22, and regulatory T (Treg) cells are depicted with their putative mechanisms of action. On the one hand, Th17 cells have been reported (more ...)
Whereas the activities of IFN-γ
are fairly well understood in the context of fungal infections, the influence of IL-17 is much more disparate. In models of C. albicans
infection, there are disparate reports concluding that Th17 cells promote protective immunity or exacerbate inflammation. IL-23 p19−/−
mice, neither of which generate functional Th17 cells, manifest heightened fungal burdens in a model of mucosal disease (46
). Fungal growth is restricted in the mucosa as a consequence of the upregulation of β-defensin 3 that exerts potent anticandidal activity. Likewise, the IL-17-IL-23 axis is necessary for optimal immunity in a model of Candida
skin infection (189
). Th17 cells may concomitantly synthesize IL-22: In particular experimental bacterial diseases, this cytokine is considered to be the principal influence on protective immunity, whereas IL-17 exerts a subordinate role (190
). However, in mucosal candidiasis, protection was largely independent of IL-22. In contradistinction, others have demonstrated that IL-22 can substitute for IL-17 in IL-17RA−/−
). It not only diminishes the fungal burden, but also maintains the integrity of the mucosal barrier in mice with candidiasis. Th17 cells are necessary for protective immunity in mice given a systemic challenge of C. albicans
. In this scenario, Th17 cells are vital for optimal recruitment of neutrophils largely through the production of CXC chemokines (192
). Although both models exemplify a need for IL-17 and Th17 cells, the basis for the antifungal effect differs strikingly between the two. Support for Th17 cells in protection against C. albicans
has been noted in humans. Some patients with chronic mucocutaneous candidiasis exhibit genetic alterations of the IL-17 pathway (193
). One individual had a deficiency in IL-17RA and others in IL-17F.
As in candidiasis, Th17 cells are a significant element in the adaptive immune response to P. brasiliensis
. In mice genetically deficient in TLR2, Th17-mediated immunity appears in conjunction with the diminished expansion of Treg cells (155
). Hence, TLR2 signaling maintains a balance of Th17 and Treg cells, and in its absence, there is a shift to a dominant Th17. However, there is a deleterious consequence to this imbalance as the host develops more severe immunopathology and tissue damage, largely as a result of an influx of neutrophils. These cells are recruited through IL-17-driven signaling despite the lower fungal burden. Although Th17 cells can promote disease pathology in models of primary, chronic pulmonary infection, vaccine-induced Th17 cells are necessary and sufficient to confer protection against secondary infection with B. dermatitidis, H. capsulatum
, and C. posadasii
. By contrast, Th1 cells are unexpectedly dispensable for vaccine immunity (79
). Vaccine-induced Th17 cells mediate protection by recruiting and activating neutrophils and macrophages to the alveolar space. Vaccinated mice with polarized Th17 cells were healthy and showed no aberrant inflammation and tissue damage in the lung despite the presence of proinflammatory Th17 cells. The lack of tissue pathology and the beneficial role of vaccine-induced Th17 cells are likely due to the rapid clearance of infection before chronic inflammation.
Because microbes seek to survive in the host, they must develop the means to evade host defenses. Viable Candida
releases a factor that inhibits IL-17 release by human peripheral blood mononuclear cells (194
). This factor, as yet uncharacterized, inhibits indoleamine 2,3-dioxygenase (IDO), but does not alter expression of PRRs that are important in the differentiation of Th17 cells. The result is an accumulation of 5-hydroxytryptophan metabolites that directly suppress IL-17 in vitro. Whether these metabolites alter expression of RORγ
c and whether this occurs at the level of the IL-17 promoter or gene remain unknown.
In contrast to the above findings, others have reported that Th17 cells dampen immunity to Candida
). An exaggerated Th17 response increases fungal burden by hindering expression of antifungal activity of neutrophils. In parallel, the exaggerated response provokes a hyperinflammatory response that induces tissue damage that does not undergo repair. The development of Th17-induced immune depression is dependent on signaling by IL-23. Heightened Th17 responses are observed in Toll IL-1R8−/−
mice infected with either C. albicans
or A. fumigatus
). By contrast, mice lacking IL-1R displayed a highly depressed IL-17 response and, consequently, a decrement in immune pathology. Thus, IL-1 signaling boosts the Th17 response, and signaling through Toll IL-1R8 is a negative regulator of IL-17 synthesis.
A reconciliation of these vastly different conclusions has not been forthcoming. Given recent evidence that Th17 cells can be segregated into pathogenic and nonpathogenic cells depending on whether they produce GM-CSF (pathogenic) or IL-10 (nonpathogenic) raises the possibility that the disparate findings may be attributable to which phenotype of Th17 cell arises in each model (197
). Because the pathogenic cells are largely driven by induction of IL-23, differences in the production of this cytokine may well account for the appearance of two distinctive populations of Th17 cells. It also is interesting to note that the MR is crucial in the outgrowth of Th17 cells in vitro from human PBMCs in response to C. albicans
, yet mice lacking this receptor are no more resistant or susceptible to this pathogen (99
). The Th17 response has not been studied in these mice, so there may well be an MR-independent pathway of Th17 cell development.
In other experimental models of fungal diseases, especially those that chiefly affect the lung, Th17 cells contribute to control of infection, but they are not essential during primary infection. In murine histoplasmosis, neutralization of IL-17 induces a modest increase in fungal burden while causing a sharp decrement in the number of leukocytes recruited to the lungs and increases in IL-6 and IL-10 (199
). However, IL-17 neutralization in IL-6−/−
mice did not alter the fungal burden, indicating that immunity in these mice is IL-17 independent. A more pronounced effect of IL-17 is noted in mice that possess IL-23 but not IL-12. These mice survive longer than those lacking IL-12 and IL-23. The increase in survival of mice capable of synthesizing only IL-23 is attributable to Th17 cells. This cell population is also not critically important in murine cryptococcosis or pneumocystosis (200
). The absence of Th17 cells causes increases in fungal burden, but the presence of Th17 cells is not requisite for survival. The emergence of robust Th1 and Th17 cells constrains C. neoformans
growth in the lungs, but it fails to halt the progression to distant sites including the central nervous system and spleen. IL-23 treatment of mice with cryptococcosis prolongs survival through the induction of Th17/22 cells, but this effect does not match that of IL-12 treatment (203