Protective Immunity against Experimental Pulmonary Cryptococcosis in T Cell-Depleted Mice

Abstract

Individuals with defects in T cell-mediated immunity (CMI) are highly susceptible to infection with Cryptococcus neoformans. The purpose of these studies was to determine if protection against experimental pulmonary cryptococcosis can be generated in T cell-deficient hosts. BALB/c mice were depleted of CD4 ؉ and/or CD8 ؉ T cells or given an isotype control antibody prior to vaccination with a C. neoformans strain, designated H99␥, previously shown to induce protection against C. neoformans infection in immunocompetent mice. Mice depleted of CD4 ؉ or CD8 ؉ T cells, but not both subsets, survived an acute pulmonary infection with C. neoformans strain H99␥ and a subsequent second challenge with wild-type C. neoformans strain H99. We observed a significant increase in the percentage of CD4 ؉ and CD8 ؉ T cells expressing the activation marker CD69 in the lungs of mice immunized with C. neoformans strain H99␥ prior to a secondary challenge with wild-type cryptococci. CD4؉ T cells within the lungs of immunized mice also appeared to acquire a predominantly activated effector memory cell phenotype (CD69 ؉ CD44 ؉ CCR7 ؊ CD45RB ؊ CD62L ؊ ) following a second pulmonary challenge with wild-type C. neoformans, compared to CD4 ؉ T cells from naïve mice. Lastly, immunization of immunocompetent mice with C. neoformans strain H99␥ prior to depletion of CD4 ؉ and/or CD8 ؉ T cells resulted in significant protection against a second challenge with wild-type C. neoformans. Our studies demonstrate that protective immunity against pulmonary cryptococcosis can be generated in immunosuppressed hosts, thus supporting the development of cryptococcal vaccines.

Vaccinations for Neuroinfectious Disease: A Global Health Priority

“…A 2011 study demonstrated that when immunocompetent mice were immunized with an interferon-gamma-producing strain of C. neoformans (H99γ) and subsequently rendered CD4 and CD8 T cell deficient, the vaccine conferred protection for up to 100 days postimmunization [68]. Separately, a recent report by Rella et al [69] describes a nonpathogenic sterylglucoside mutant strain of C. neoformans that conferred complete protection against lethal doses of both C. neoformans and C. gattii in mice.…”

Antifungal Activity of Plasmacytoid Dendritic Cells against Cryptococcus neoformans In Vitro Requires Expression of Dectin-3 (CLEC4D) and Reactive Oxygen Species

“…Pulmonary C. neoformans infections were initiated by nasal inhalation as described previously (11,12,22). Mice were anesthetized with 2% isoflurane using a rodent anesthesia device (Eagle Eye Anesthesia, Jacksonville, FL) and were then given a yeast inoculum of 1 ϫ 10 4 CFU of C. neoformans strain H99 or H99␥ in 50 l of sterile PBS pipetted directly into the nostril.…”

“…Experimental murine studies using a C. neoformans strain engineered to express gamma interferon (IFN-␥), designated H99␥, have shown that pulmonary infection with H99␥ results in the induction of Th1-type cytokine responses in the lung, lymphocyte recruitment, reduced fungal burdens, and complete protection against an otherwise lethal challenge with C. neoformans (11)(12)(13). Cell-mediated immunity (CMI) by Th1-type CD4 ϩ T cells is important for the induction of protective immunity against C. neoformans (12,14).…”

Fungal Vaccines and Immunotherapeutics

“…In a more recent study, depletion of CD4 þ or CD8 þ T cells during the immunization phase ( primary infection with H99g) or secondary lethal infection protected 100% of mice from mortality. However, when both CD4 þ and CD8 þ T cells were depleted during immunization with H99g or secondary infection, mortality reached 100% (Wozniak et al 2011). Although the H99g strain vaccine could not be used in humans, it does serve as a proof of concept for live vaccination strategies, whereby pathogens are genetically engineered to produce cytokines that enhance host-protective responses.…”