Cellmediated Immunity

Cell-mediated immunity (CMI) has an important role in host defense against cryp-tococcosis. Not only is CMI important to initial infection with Cn, it is maintained during persistent, secondary infections as well (Lindell et al., 2005, 2006). Comparison of high- and low-virulent Cn strains in vivo shows that infection with the more virulent strain induces a rapid DTH response to the cryptococcal antigen CneF, indicative of CMI activation (Blackstock et al., 1999). T cells proliferate in vitro in response to Cn, especially CD4+, but also CD8+ T cells. Furthermore, depletion experiments with mAbs against CD4 or CD8 demonstrated that CD4+ T cells are required for CD8+ T cell proliferation, but not vice versa (Syme et al., 1997). A more detailed analysis of the T cell response to Cn infection shows that a large diversity of T-cell receptor Vß subsets proliferate, especially for CD4+ T cells (Lindell et al., 2006).

CD8+ cells are also involved in CMI to Cn. A0-/-mice (C57BL6/J background) that lack major histocompatibility complex (MHC) II and therefore CD4+ T cells can be vaccinated with a low-virulent Cn strain and subsequently survive challenge with a low dose of Cn cells. When the mice are also given mAb to CD8, the effect of immunization is somewhat blocked, indicating resistance was partially CD8 dependent (Aguirre et al., 2004).

The role of cell-mediated immunity in host response to Cn is further illustrated by the finding that MHC genotype affects the host response to Cn. Strains of mice differing in the MHC locus and infected with Cn have different susceptibilities to the fungus, as assessed by fungal burden in the liver (McClelland et al., 2003b). Furthermore, when Cn is passaged in these mice, the time to death decreases at different rates in the different MHC backgrounds, showing the influence of MHC on host response to Cn (McClelland et al., 2004b).

Another component of CMI, co-stimulatory T cell surface proteins such as CD40, play a role in immunity to Cn. CD40-/-mice infected with Cn have higher lung fungal burdens and reduced lung inflammatory cell infiltration compared to wild type. Cultured splenocytes from these mice produce lower levels of Th1 cytokines (Pietrella et al., 2004). The role of CD40 signaling is further demonstrated by treating infected animals with a combination therapy of anti-CD40 Ab and interleukin (IL)-2. The treated mice have increased survival and fewer Cn in the brain and kidney (Zhou et al., 2006). The co-inhibitory receptor CTLA4 also functions in the T cell response to Cn as CTLA4 expression increases on the surface of T cells in response to Cn (Pietrella et al., 2001b). Anti-CTLA4 antibodies administered to infected mice increase the DTH response to Cn and reduce the fungal burden. When combined with CneF immunization, the antibodies increase the survival of mice infected with Cn (McGaha & Murphy, 2000).

A strong Th1 response is clearly required for effective host defense against Cn. When mice are infected with high- or low-virulent Cn strains and the cytokines produced by cultured spleen cells in response to CneF are measured, the low-virulent strains elicit more Th1 cytokines (IFN-y and IL-2) later in infection compared to the high-virulent strains, showing the importance of a sustained Th1 response against Cn (Blackstock et al., 1999). Measurement of cytokines in bronchoalveolar lavage fluid of such mice indicates that the high virulent strain induces higher levels of IL-4, suggesting a Th2 response is associated with a negative outcome of infection (Abe et al., 2000). Additionally, experimental treatment of mice that promotes a strong Th1 response correlates with reduced cryptococcal burden and inflammation (Edwards et al., 2005).

Studies with knockout mice show the importance of specific Th1 cytokines. IL-18-/-mice infected with Cn have reduced lung and brain fungal clearance, DTH response to Cn, and Th1 cytokines, including IFN-y (Kawakami et al., 2000). Other host factors are required for the induction of the Th1 response, including urokinase-type plasminogen activator (uPA). Mice lacking uPA are unable to mount an adequate Th1 response against Cn infection, and lung histopathology shows that the alveolar spaces are filled with macrophages containing Cn. In addition, these mice have smaller lymph nodes and less T cell proliferation (Gyetko et al., 2002).

In contrast, a Th2 response is less effective against Cn. In the absence of IL-10, a Th2-promoting cytokine, mice survive Cn infection longer (Blackstock et al., 1999). Results with another Th2 cytokine, IL-4, are more complex. IL-4 -/-mice have reduced DTH to CneF with Cn infection, indicating a need for IL-4 in CMI against Cn. However, cultured spleen cells from infected mice stimulated with CneF produce more IL-2 and IFN-y and less IL-5 and IL-10, indicating an enhanced Th1 response in the knockout mice compared to wild type. Despite this, there are no survival differences in the mouse strains when infected with Cn, except that the knockout mice survive better when primed with CneF before infection (Blackstock & Murphy, 2004b).

Since Cn usually infects the CNS, the role of CMI in the CNS is also studied using the intracerebral (i.c.) infection model, in which mice are infected by injecting fungal cells directly into the brain, eliminating the complicating factor of dissemination in interpreting results. When mice are immunized with CneF and subsequently infected i.c., the fungal burden in the lung, brain, and spleen is lower than the control. In addition, more leukocytes are present in the brain, especially CD4+ T cells and macrophages. Moreover, antibodies to CD4 and IFN-y increase the fungal burden in the brain (Buchanan & Doyle, 2000) and CneF-immunized mice have increased expression of a number of chemokines and Th1 cytokines in the brain after i.c. infection (Uicker et al., 2005). Using mouse strains that favored either Th1 or Th2 response, Huffnagle and McNeil (1999) found that Th1-polarized mice have reduced infection of the CNS. Other studies show the importance of MHC in fighting Cn in the CNS. Adoptive transfer experiments in MHC class II deficient mice show that CD4+ T cells require interaction with MHC II on perivascular microglial cells in the CNS (Aguirre & Miller, 2002). Together, these data show that CMI is important in fighting Cn in the CNS.

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