Excellent reviews have recently been published regarding the immune response during trematode and nematode infections (2,21,36). However, the class cestoda has been largely neglected, even though these parasites produce important threatening diseases around the world. The infection of the intermediate hosts by the metacestode stage of Taenia species, and especially T. crassiceps, appears to be a very good model to unveil some of the mechanisms of the host–parasite interplay in cysticercosis. Taenia crassiceps cysticercosis naturally affects rodents and the final hosts are canines. Nevertheless, there are reports demonstrating that immunocompromised humans can develop T. crassiceps cysticercosis (37,38). The metacestode stage of T. crassiceps has the advantage of an asexual budding reproduction (39). This biological phenomenon has been useful in generating long-lasting infections in laboratory mice, where regularly the parasite is inoculated i.p., and after a few weeks, hundreds of macroscopic parasites can be reached from the peritoneal cavity. Additionally, antigenic similarities have been very well established between T. solium and T. crassiceps metacestodes (40). Thus, sera from human patients suffering from neurocysticercosis positively recognize T. crassiceps antigens. After initial infection with T. crassiceps cysticerci, a rapid but transient Th1 response is observed in the host (41), and the immune response is sequentially biased to a Th2 response following a period of a mixed Th1/Th2 response (42). Along with this dynamic immune response, macrophages recruited in the peritoneal cavity change as infection progresses. Peritoneal macrophages (F4/80+) isolated at different times after challenge with T. crassiceps have been used as APC and tested for their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of IL-12 and NO, paralleled with low levels of IL-6 and have the ability to induce strong antigen-specific CD4+ T cell proliferation in response to unrelated antigens (5). In contrast, macrophages from chronic infections produced a different pattern of cytokines and chemokines, associated with a poor ability to induce antigen-specific proliferations in CD4+ T cells. Failure to induce proliferation was not due to deficiencies in the expression of accessory molecules, since MHC-II, CD40 and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed (5). Besides these molecules, another set of markers has recently been found elevated in the peritoneal macrophages from T. crassiceps-infected mice (Table 1), such as high expression of MR, the C-type lectins (mMGL1 and mMGL2), Arg-1, Fizz1, Ym1 and TREM-2, confirming that these macrophages are alternatively activated (43,44). Macrophages from chronic infections were able to bias CD4+ T cells to produce IL-4, but not IFN-γ, contrary to macrophages from acute infections, just like those described previously in nematode infections. Furthermore, studies using STAT6−/– mice revealed that the STAT6-mediated signalling pathway was essential for the expansion of AAMφ in murine cysticercosis (5,45). More recently, it has been shown that IL-4Rα−/– mice were also unable to induce AAMφ after T. crassiceps infection (14). Together, these studies performed by independent groups agree with the early observation of IL-4 dependency for Brugia and Schistosoma AAMφ induction.
Another striking observation has been the ability of AAMφ isolated from T. crassiceps-infected mice to inhibit the proliferative response of naïve T cells (44). Apparently, this effect involves a cell contact-dependent pathway. Supporting evidence for cell contact-dependent involvement was associated with increased expression of PD-L1 and PD-L2 in AAMφ. The participation of the PD-1 pathway was tested by blocking PD-L1 and PD-L2, or PD-1 by adding mAbs to co-cultures of naïve T cells with AAMφ from T. crassiceps-infected mice. Blockade of the PD-1 pathway significantly reduced AAMφ suppressive activity and therefore T cells proliferated normally. These data indicate that PD-L1 and PD-L2 are directly involved in the cell contact suppressive activity of AAMφ from T. crassiceps-infected mice. Whether this will also be true for the contact-dependent suppression seen in nematode infection is yet to be tested.
AAMφ induced by T. crassiceps infection were also demonstrated to suppress the specific response of CD4+ DO11·10 cells to OVA peptide stimulation when normal macrophages were used as APC. Again, the blockade of PD-1 re-established the peptide-specific proliferative response of CD4+ DO11·10 cells. Therefore, AAMφ can participate as a third party suppressive cell. Similarly, the presence of AAMφ in a DC-mediated mixed lymphocyte reaction was enough to inhibit the response of CD4 cells from a different genetic background (44). Thus, AAMφ induced during T. crassiceps infection suppress immunological events mediated through distinct molecular mechanisms that potentially may induce strong proinflammatory responses. It was also demonstrated that the PD-1/PD-L pathway participates in modulating anti-Taenia-specific cell proliferative response.
Initial support for in vivo AAMφ induction by Taenia glycoproteins has recently been reported (46). Together with thioredoxin from F. hepatica, it seems that helminth-derived molecules can induce these types of cells in wild-type mice; however, the role for IL-4 in the antigen induction of AAMφ needs to be clarified.
Translating these series of results to the immune balance in neurocysticercosis, it is therefore possible that the presence of AAMφ with suppressive activity and low proinflammatory profile may be necessary to turn off possible dangerous inflammatory responses in the brain. In fact, a series of reports suggest that active inflammatory responses in neurocysticercosis leads to pathological symptoms (47), whereas a silent (anti-inflammatory) immune response has been associated with asymptomatic neurocysticercosis (48,49).