484

The T cell response against fungal infections

Luigina Romani
A variety of pathological conditions, including impaired of human pathogenic fungi to grow in different forms in
immune function, is believed to underlie host susceptibility vivo, requiring distinct habitats and resulting in different
to fungal infections and to determine both the severity and life cycles, or to co-evolute as commensals, thus possibly
the characteristics of the associated pathology. Although the evading host defenses, may have resulted in an expanded
redundancy and the interdependence of antifungal responses repertoire of cross-regulatory antifungal responses, whose
may not favor the proper dissection and appreciation of proper integration allows for the generation of an optimal
individual effector mechanisms, the T helper type 1/type 2 antifungal immune response. In addition, virtually all
paradigm of acquired immunity to fungi is proving essential for medically important fungi carry an impressive array of
a better understanding of the host response from a regulatory macromolecules with immunomodulatory functions on
perspective. The recent understanding of the importance of their cell surfaces that play significant roles in the
the different T helper cell subsets in fungal infections and the fungus-host interaction and the ensuing immunity. Nev-
increasing appreciation of the reciprocal regulation between ertheless, cell-mediated immunity (CMI) mediated by T
the innate, humoral, and adaptive immune systems in the lymphocytes and nonspecific cellular immunity mediated
development of optimal antimicrobial immunity have offered by macrophages, neutrophils, and natural killer cells are
us new clues which may lead to an understanding of T cell considered to provide the main defenses against fungi
dependent immunity to fungi. (reviewed in [1]). Most opportunistic mycoses occur in
individuals with defective innate and/or adaptive cellular
immunity (reviewed in [2]).
Addresses
Microbiology Section, Department of Experimental Medicine and Protective and nonprotective T cell r e s p o n s e s
Biochemical Sciences, University of Perugia, Via del Giochetto,
06122 Perugia, Italy; e-mail: Iromani@unipg.it to fungi
T h e recognition of the involvement of different T helper
Current Opinion in Immunology 1997, 9:484-490 (Th) cell subsets in fungal infections (reviewed in [1])
http://biomednet.com/elecref/0952791500900484 offers new perspectives to our understanding of the T cell
response to fungi and its immunoregulation. The pattern
© Current Biology Ltd ISSN 0952-7915
of CMI and the humoral immune responses occurring in
Abbreviations many fungal infections strictly mirrors that predicted by
ABPA allergicbronchopulmonary aspergillosis
the preferential activation of T h l or Th2 effector cells,
CMI cell-mediatedimmunity
DTH delayed-typehypersensitivity respectively, following a fungal infection, as discussed
IFN interferon below.
IL interleukin
MCP monocytechemotactic protein Development of CMI, as assessed by skin testing, lym-
TCR T cell receptor
Th T helper phoproliferation assays, and cytokine production (namely
TNF tumor necrosis factor interferon [IFN]-~/and interleukin [IL]-2) by T h l cells
V variable in response to relevant fungal antigens, occurs upon
exposure to airborne environmental fungal elements or as
a consequence of skin and mucosal fungal colonization
Introduction [2]. In the case of infection by endemic dimorphic fungi,
Fungi are associated with a wide spectrum of diseases the occurrence of CMI is also evident in the formation of
in humans and animals, ranging from benign colonization an epithelioid granuloma [2]. In experimental models of
and allergy to life-threatening diseases and autoimmunity. fungal infections, the extent and effectiveness of CMI in
A variety of underlying conditions, including impaired mediating protection varies according to the host genetic
immune status, is believed to account for the susceptibility background, the route and site of infection, the nature
to fungal infections and to determine both the severity and of the local immune response, and the type of infecting
the characteristics of the associated pathology. A thorough organism [3°]. Antifungal CMI can be adversely modulated
appreciation and understanding of how the normal host at both the inductive and effector immune response
resists fungal invasion and of the specific immune defects levels, particularly by inhibitory cytokines produced
present in patients with mycoses are fundamental for the mainly by Th2 cells. Th2 cell responses, however, are
development of rational approaches to immunodiagnosis not always detectable during the course of progressive
and therapy of these infections. Defining the relative fungal infections [3°]. A positive correlation has been
contributions of each component of the immune system found between the occurrence of T h l cell responses and
to antifungal defense may be both restrictive and difficult, the resistance to experimental infections by Coccidioides
however, because of the interdependence and redundancy immitis [4,5 ], Paracoccidioides brasiliensis [3 ",6 ], Histoplasma
of the immune defense mechanisms. Indeed, the ability capsulatum [3°,7,8,9"], Blastomyces dermatitidis [2], Crypto-
 The T cell response against fungal infections Romani 485

coccus neoformans [3°,10], Aspergillus fumigatus [11,12], and antigens during infection, it is the development of
Candida albicans [13°,14-16,17°]. T h e induction of such inflammatory CMI, which correlates with the delayed-type
T h l responses requires the presence of IL-12, as revealed hypersensitivity ( D T H ) to dermatophyte antigens, that
by the ability of the exogenous administration of IL-12 is associated with clinical cure and protection [32].
to induce protective antifungal effects in mice with or In fact, the absence of a D T H reactivity, associated
without impaired T cell immunity ([9°]; reviewed in [18]) with the presence of a Th2 type immune response,
and by the failure of IL-12p40 knockout mice to mount such as an increase in nonspecific IgE and specific
a protective T h l response to C. albicans (L Romani, IgG4, prevents an effective response and predisposes
unpublished data). Recent data indicate that TCRc~[3 cells, nonatopic patients to chronic or recurrent Trichophyton
of either CD4 or CD8 phenotypes, are important for rubrum infection [33]. Although it has been reported
the containment of murine Pneumoo,stis carinii infection that the development of immediate hypersensitivity may
[19,20], and adoptive transfer of CD4 ÷ lymphocytes interfere with the development of a protective D T H
sensitized to the major surface glycoprotein of this fungus response [32], in this study [33] there was no evidence
confers protection in the rat [21]. Although elimination of for the presence of immediate hypersensitivity. In patients
P carinii infection appears not to require I F N - y [22], a with atopic dermatitis, induction of IgE, IL-4, and IL-10
highly activated phagocytic system is insufficient for the synthesis occurs in response to both protein and mannan
prevention and cure of P carinii infection in the absence antigens of Pityrosporum ovale [34,35]. A single protein
of CD4 + al3 T lymphocytes [23]. of Trichophyton tonsurans, however, is endowed with the
ability to elicit either T h l or Th2 cytokines in subjects
Although the complexity of the spectrum of fungal with delayed or immediate hypersensitivity, respectively
diseases in humans may not be easily accommodated by [36,37], thus suggesting that factors other than antigens
the deterministic and apparently reductionistic approach may determine whether T h l or Th2 cells respond at the
provided by the T h l / T h 2 paradigm of acquired immunity cutaneous level. Whether nonprotective Th2 responses
in experimental fungal infections, there is evidence for arise as a consequence of chronic fungal infections,
the occurrence of predominant, selective T h cell responses as suggested [32], and whether the pathology of the
in human fungal diseases. A possible association between disease is the cause or consequence of the observed
the predominance of Th2 rather than T h l responses immune deviation, remains unsolved. Likewise, the causal
and Candida infection has been shown in patients with relationship between atopy and chronic dermatophytoses
chronic mucocutaneous candidiasis, suggesting that the is an open issue, although both immediate hypersensitivity
manifestation seen in these patients (i.e. impairment to dermatophyte antigens and a higher than expected
of CMI, high levels of Candida-specific antibodies, and incidence of atopy have been found in patients with
susceptibility to intracellular bacterial infections) could be chronic dermatophytosis (reviewed in [32]).
the consequence of imbalanced cytokine production and
regulation [24°,25°]. In HIV infection, the production of In addition to T lymphocytes bearing c~I3TCRs, ySTCR
IFN-y [26] and, to a lesser extent, IL-12 [27] by peripheral T cells may play an important role in antifungal host
blood mononuclear cells is reduced in response to C. defense mechanisms by acting as a first line of defense
albicans and C. neoformans, as compared with seronegative at the mucosal level. Polyclonal y8 T cells were found
donors, thus emphasizing the decline of CMI in this to be expanded in the gastric mucosa of mice infected
infection. In patients with C. immitis meningitis, CD4 ÷ orally with C. albicans, while T C R y-chain knockout
T lymphocytes from the cerebrospinal fluid exhibit a mice were susceptible to mucosal orogastric candidiasis,
significant, antigen-specific, proliferative response, which although to a lesser extent than c~13 T cell deficient mice
was observed early in the course of the disease as (J Jones-Carson, A Vazquez-Torres, T Warner, M Sandor,
well as after remission [28]. In contrast, the content of E Balish, abstract 310, Keystone Symposia on Innate
cerebrospinal fluid antibodies against a 33 kDa coccidioidal Immunity: Non-clonal Host Defense Mechanisms, Park
antigen increases as infection progresses and decreases City, Utah, January 1997). In humans, y8 T cells from
following successful antifungal chemotherapy [29]. These unexposed individuals respond to protein antigens of P
results are in agreement with the pattern of CMI and brasiliensis and produce factors supporting the growth and
humoral immunity observed in coccidioidomycosis, in differentiation of B cells [38].
which the degree of CMI directly correlates with the level
of resistance to the fungus, whereas antibody production Fungal anergy, allergy and autoimmunity
correlates inversely with resistance [2,30"]. In response to Active suppression of CMI has been associated with a
P brasiliensis protein antigens in vitro, human naive CD4 ÷ number of fungal diseases. As discussed above, anergy may
TCRo~I3 cells proliferate and produce IL-2 in an M H C result as a consequence of immune deviation: the induc-
class II restricted manner [31]. To what extent this finding tion of Th2 cell responses downregulating effector T h l
correlates with protective immunity is, as yet, unclear. lymphocytes. A number of fungal toxins with a broad range
of immunosuppressive properties have been described,
Regarding infection with dermatophytes, although the however [2]. Gliotoxin, a secondary fungal metabolite of
host develops a variety of antibodies against dermatophyte A. fumigatus and other pathogenic fungi, exhibits profound
486 Immunityto infection

immunosuppressive activity in vivo [2]. These effects can In addition to the ability of fungal cells to directly
be explained by its ability to inhibit activation of the activate T lymphocytes, which T cell responses occur
transcription factor NF-~B in T and B cells in response in vivo to fungi is likely to depend on multiple factors
to a variety of stimuli [39°]. Among the plethora of fungal including events occurring at the level of nonadaptive
constituents or products with immunosuppressive activity immunity, such as the production of cytokines and
in candidiasis, the immunosuppressive p43 protein was chemokines. Fungal cells possess a variety of cell surface
recently found to act as a major virulence factor in the analogs of both the integrin family and complement
pathogenesis of experimental candidiasis [40]. In murine receptors which may facilitate attachment (opsonization)
pulmonary cryptococcosis, melanin produced by a highly and phagocytosis by phagocytic cells. In vivo studies
virulent strain inhibits both the T h l and Th2 responses to have provided convincing evidence that the complement
the infection [41]. In mice infected with H. capsulatum, the system is an important component of innate resistance
suppressed lymphoproliferative response to both specific to fungi, through opsonization and the induction of
antigens and mitogens is restored by inhibiting nitric oxide an inflammatory immune response [49]. T h e specific
production [7]. mechanisms by which complement activation mediates
resistance in the different fungal infections are still poorly
Fungi are associated with a number of allergic disorders in understood, however. This is an interesting area of study
humans [2]. In addition to the association between atopy which deserves further investigation.
and dermatophytosis discussed above, allergic bronchopul-
monary aspergillosis (ABPA) is a hypersensitivity disease As CD4 + T h cell differentiation in vivo is critically affected
associated with A. fumigatus colonization [2]. T cell clones by the tissue fungal load [17°,50], an important role for
from patients with ABPA are of the Th2 type, as they phagocytic cells can be traced to their ability to control
produce IL-4 and little or no IFN-7 in response to the fungal growth by several antifungal effector mechanisms.
Asp f 1 allergen [42]. In a murine model of ABPA, IL-10 In mice with X-linked chronic granulomatous disease and
limited the extent of the Th2 responses and the IFN-y absent respiratory burst, however, abnormalities in both
production induced by inhaled A. fumigatus antigens, thus the host defense and inflammatory immune responses
resulting in reduced airway inflammation [43]. are detected even to sterilized Aspergillus hyphae [51],
thus indicating that the effect of early fungicidal events
In allergy to A. fumigatus, strong humoral and CMI may go beyond the control of microbial infectivity. In
have been detected towards a human cross-reactive this regard, the production of proinflammatory cytokines,
antigen, identified as manganese superoxide dismutase such as tumor necrosis factor ( T N F ) - a and IL-6, and of
[44°]. Whether the autoimmune reactions are due to the chemokine monocyte chemotactic protein (MCP)-I by
molecular mimicry between microbial antigens and self phagocytic cells, directly affects the subsequent T cell
proteins or to bystander sensitization to self proteins by response to C. neoformans [52,53] and C. albicans [15,54]. In
epitope spreading, remains to be elucidated. Of relevance, a murine model of pulmonary cryptococcosis, TNF-ct acts
the detection of autoimmune reactivity has also been as a proximal mediator of phagocytic MCP-1 production,
associated with some candidal diseases (reviewed in [45]). and leads to MCP-1 activity which includes both the
local recruitment of leukocytes and the production of
proinflammatory cytokines [52]. In humans, C. neoformans
T cell activation in f u n g a l infections acts as a potent stimulator of MCP-1 production in
Although the direct stimulation of T cell IFN-y release monocytes but not in bronchoalveolar macrophages [55].
by fungal cells has been demonstrated in vitro [46], its Production of MCP-1 also occurs in the response of murine
relevance in vivo remains to be clarified. Nevertheless, macrophages [56] and endothelial cells [57] to C. albicans.
this finding suggests that fungi may possess molecules Macrophage secretion of MCP-1 occurs in a different
capable of interacting directly with T cells. T h e recent manner to that of proinflammatory cytokines, in that it is
evidence that C. albicans induces the selective expansion independent of stimulation of the mannose receptor on
of T lymphocytes bearing a particular variable (V) domain these cells [56].
specificity, V138, raises the possibility that one such
molecule may exhibit superantigen activity [47]. Differen- An important immunoregulatory role in fungal infections
tial expansion of T lymphocytes of a particular V region has recently been attributed to neutrophils. By producing
specificity is associated with patterns of susceptibility and directive cytokines, such as IL-10 and IL-12, these cells
resistance to C. albicans infection in mice (L Romani et influence antifungal T h cell development, as evidenced
al., unpublished data). This finding, together with that of by the inability of Canclida-infected, neutropenic mice to
an anticandidal protective T h l response induced by the mount a protective T h l response [58,59",60",61]. Such a
systemic administration of staphylococcal enterotoxin B response, including the antifungal effector functions of
[1], points to a potential role for CD4÷ T C R V~8 ÷ T cell macrophages, could be efficiently restored by replacement
anergy in the modulation of acquired immunity to Candida therapy with IL-12 [58,59",60°,61]. Therefore, the ability
[48]. Indeed, anergy reversal by treatment with IL-2 is of neutrophils to participate in T h selection in fungal
associated with a high susceptibility to the infection [48]. infections may also include a permissive role on the
 The T cell response against fungal infections Romani 487

antifungal effector and immunomodulatory functions of T cell mediated protection in fungal infections
macrophages. Production of IL-12 by neutrophils from Within a conceptual framework provided by the T h l / T h 2
C. albicans infected mice is impaired upon iron overload, paradigm of immunity in fungal infections, a unifying
a finding that suggests a possible role for defective view of phagocyte-dependent immunity to fungi may be
neutrophil secretory and effector functions in the suscep- envisioned. T h l and Th2 cells, by critically providing
tibility to fungal infections by patients with disturbed iron cytokines with activating and deactivating signals for
metabolism [62]. Although the production of IL-12 by fungicidal phagocytes, may be instrumental in mobilizing
neutrophils occurs in the absence of IFN-y (L Romani, and activating the proper anticandidal effector mechanism
unpublished data), it is potentiated by IFN-y priming, at the site of infection. Therefore, phagocyte-dependent
suggesting a positive amplification loop in early IL-12 resistance to fungi is regulated at the effector level by
production by neutrophils in response to C. albicans cells sets of opposing cytokines, such as IFN-y and IL-4 or
or its mannan component [18,61]. These results confirm IL-10 [1]. Indeed, IL-10 suppresses the oxidative burst
recent data from HIV-positive individuals, in which IL-12 and the antifungal activity of human mononuclear cells
production by peripheral mononuclear cells in response against A. fumigatus hyphae [79], and suppresses the
to fungi is potentiated by priming with IFN-y [26]. production of the proinflammatory cytokines TNF-(x and
The recent evidence that cognate CD40-CD40 ligand IL-113 in response to C. neoformans or C. albicans [80,81].
interactions between macrophages and CD4 ÷ TCRo~I3 cells In response to Aspergillus, the effects of IL-10 were partly
is essential for immunocompetence against P carinii [63], counteracted by IFN-y [79], a finding which may have
suggests the importance of this additional mechanism of important therapeutic implications, particularly in patients
IL-12 production and costimulation of CD4 ÷ T h l cells in with impaired CMI and increased risk for a chronic form
fungal infections. of pulmonary aspergillosis, such as HIV-infected patients.

The finding that the CD40 molecule is expressed on One less obvious mechanism by which T lymphocytes
B cells may suggest an important extended role for may affect the clearance of pathogenic fungi is through
these cells in the development of CMI to fungi. Recent direct interaction with fungal cells to mediate death or
studies indicate that the development of protective CMI limit replication of the microorganism [82,83]. Both CD4 ÷
to C. albicans [64], C. neoformans [65], and P carinii [66] is and CD8÷ T cells are endowed with the ability to bind
impaired in B cell deficient mice. Interestingly, in murine and exert fungal growth inhibition that appears to occur
candidiasis, mucosal but not parenteral immunization with through as yet poorly defined mechanisms. Although
C. albicans leads to a B cell independent [67"], but a the antifungal capacity of T lymphocytes increases as
CD8 ÷ T cell dependent [68], induction of protective a consequence of immunization to fungal cells [3"], its
memory T cells. T h e mechanisms by which the B cell relevance in vivo remains an unsolved issue.
compartment may affect the development of protective
CMI to fungi are becoming clearer. Both protective and Conclusions
nonprotective effects are observed upon passive antibody T h e T h l / T h 2 paradigm of acquired immunity to fungi
administration in mice with fungal infections [69]. T h e is essential for a better understanding of the immuno-
evidence that opsonizing antibodies to a distinct epitope of regulation which occurs during fungal infections. As the
the C neoformans capsule may increase yeast phagocytosis different T h cell subsets are endowed with the ability
by macrophages, ultimately potentiating T cell activation, to release a distinct panel of cytokines, capable of
indicates that both epitope specificity and antibody delivering activating and deactivating signals to effector
isotype are important determinants of antibody function phagocytes, the activation of an appropriate T h subset
[70-72,73°]. Interestingly, the evidence that antibody may be instrumental in the generation of a successful
function in vivo in mice with cryptococcosis is strongly immune response to a fungal pathogen. In its basic
dependent on host cellular immune functions [74"], conception, the paradigm calls for: first, an association
strongly reinforces the concept that antibodies mediate between the T h l responses and the onset/maintenance
their function through their effects on cellular immunity of phagocyte-dependent immunity, critical for opposing
[73"]. Similarly, only monoclonal antibodies recogniz- the infectivity of commensals and for clearing pathogenic
ing a specific epitope within the phosphomannoprotein fungi from infected tissue; second, the active suppression
complex of C. albicans protect highly susceptible mice of CMI, associated with fungal infections and diseases,
against disseminated candidiasis [73",75]. A recent clinical as a consequence of anergy and/or immune deviation;
observation suggests that naturally occurring fungicidal third, the reciprocal regulation of T h l and Th2 responses,
antibodies, mimicking the activity of microbial products, resulting in a dynamic balance between the two types
such as a yeast killer toxin, are present in humans and may of reactivity that may operate from commensalism to
participate in the host defense against mucosal candidiasis infection and its associated pathology. With a view to either
[76"] and other fungi [73"]. Altogether, these results controlling fungal infectivity or opposing fungus-associated
indicate that humorai immunity, either independently or immunopathology, the promotion of fungus-specific T h l
through augmentation of protective CMI, may contribute responses appears to be a realistic objective in the de-
to host resistance to fungi [73",77,78"]. velopment of vaccines, immunodiagnosis, and therapy of
488 Immunity to infection

human fungal infections. Thus, probing fungal antigens for and C D 4 + T helper cell 1 development in interleukin 6-
deficient mice infected with Candide albicans. J Exp Med 1996,
their ability to elicit protective cellular responses [84] and 183:1345ol 355.
finding new antifungal therapeutic strategies, including 16. JansenJ, Warner T, Johnson C, Balish E: Oral immunization of
the combination of antifungal drugs with cytokines and/or mice against candidiasis. J Infect Dis 1996, 174:133-140.
cytokine antagonists [9",85"], may eventually represent 17. Mencacci A, Spaccapelo R, Del Sero G, Enssle K-H, Cassone A,
promising antifungal approaches. • Bistoni F, Romani L: CD4 + T-helper-cell responses in mice
with low-level Candida albicans infection. Infect Immun 1996,
64:4907-4914.
Acknowledgements This paper shows the dynamics of the development of the Th cell response
in mice with a low- to moderate-level of C. albicans infection. Th2 responses
I would like to thank Eilecn Zannetti for superb secretarial and editorial are only observed by increasing the fungal load. Induction of Thl anti-
assistance in the preparation of this manuscript. "l'his work was supported candidal responses occurs in mice with a low level C. albicans infection.
by IX AIDS Project (contract no. 9404-3I), Italy. The Tht response, however, does not result in the development of a memory
protective response, which correlates instead with antigen persistence in
vivo and requires IL-4.
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