# Cryptococcus: History, Epidemiology and Immune Evasion
## 12 Immune Response against Cryptococcosis
### Cell Response against the Infection  
The internalized fungus survives well at the acidic pH of the phagolysosome and subverts its maturation machinery, as already described [211]. In this sense, some analyses were carried out with regard to autophagy markers during an infection caused by _C. neoformans_ and it was noted that unlike in other pathogenic yeast species, cryptococosis caused by the selective intracellular pathogen _C. neoformans_ is less severe in the absence of autophagy [239]. Furthermore, NLRC4 inflammasome-mediated activation of caspase-1 during _C. gattii_ cryptococosis increases pyrotosis in phagocytes and affects their phagocytic capacity by inhibiting the yeast intracellular parasitism [240]. [PERSON] and colleagues even describe that _C. gattii_ has a greater resistance to oxidative stress generated by the antifungal activity of neutrophils than _C. neoformans_[241]. In addition to the control of cryptococosis by the innate immune response, the adaptive response also plays a key role. During cryptococosis, where the cytotoxic role of CD8\({}^{+}\) T lymphocytes in infection control has already been reported, interestingly, this mechanism is dependent on activation by CD4\({}^{+}\) T lymphocytes and the production of IL-15, a cytokine responsible for the increase in the cytotoxic activity of CD8\({}^{+}\) T lymphocytes in the immune microenvironment [242]. Furthermore, it is well described, not only for _C. gattii_ but also for other pathogenic fungal species, that targeting the Th1/Th17 activation axis is important for fighting infection and for the better clearance of the fungal load in the host, with the production of cytokines, such as IFN-\(\gamma\) and IL-17, associated with this phenotype [221] (Figure 3). Therefore, T lymphocyte populations mediate infection control by acting directly on the yeast and directing the antifungal immunity by controlling the cytokine profile in the immune microenvironment; however, the mechanisms orchestrated during the immunopathogenesis of cryptococosis are still discrerely elucidated, especially in the context of infection caused by _C. gattii_. Along these same lines, the role that the B lymphocyte population plays during this infection is still poorly understood. However, there are some data that show the importance of this population of cells in the production of antibodies. For instance, it has been observed that B lymphocytes produce IgM antibodies that have the ability to induce the Th1 profile and assist in the recruitment of macrophages and phagocytosis during pulmonary _C. neoformans_ cryptococosis [243]. Specifically, natural IgM produced by B-1 lymphocytes appears to mediate antifungal immunity in the early stages of infection caused by _C. neoformans_[244; 245]. However, not only the production of natural IgM seems to be related to the reduction in the predisposition to the formation of titan yeasts, but the population of B-1 lymphocytes seems to limit this phenotype that is associated with the worsening of the _C. gattii_ and _C. neoformans_ infection [187; 190; 246]. This demonstrates the importance that the B lymphocyte population as a whole seems to have in anticrypococcal immunity, especially when it is associated with the clinical description of a higher incidence of _C. neoformans_ cryptococosis in human individuals who have compromised B lymphocyte populations [247; 248]. The populations of B lymphocytes are responsible for maintaining the humoral response in the body, helping to control infections caused by a countless range of pathogens [249]. Among them, the subpopulation of B-1 lymphocytes has a decisive role in the control of fungal infections, being recently studied, during the progression of _C. gattii_ and _C. neoformans_infection [245,246]. B-1a and B-1b populations have been reported to produce natural antibodies against the capsular components of _Streptococcus pneumoniae_, attenuating the infection [250].