T cells augment monocyte and neutrophil function in host resistance against oropharyngeal candidiasis

Abstract

The purpose of this study was to identify the cell populations involved in recovery from oral infections with Candida albicans. Monoclonal antibodies specific for CD4+ cells, CD8+ cells, and polymorphonuclear leukocytes were used to deplete BALB/c and CBA/CaH mice of the relevant cell populations in systemic circulation. Monocytes were inactivated with the cytotoxic chemical carrageenan. Mice were infected with 10(8) C. albicans yeast cells and monitored for 21 days. Systemic depletion of CD4+ and CD8+ T lymphocytes alone did not increase the severity of oral infection compared to that of controls. Oral colonization persisted in animals treated with head and neck irradiation and depleted of CD4+ T cells, whereas infections in animals that received head and neck irradiation alone or irradiation and anti-CD8 antibody cleared the infection in a comparable fashion. The depletion of polymorphonuclear cells and the cytotoxic inactivation of mononuclear phagocytes significantly increased the severity of oral infection in both BALB/c and CBA/CaH mice. High levels of interleukin 12 (IL-12) and gamma interferon (IFN-gamma) were produced by lymphocytes from the draining lymph nodes of recovering animals, whereas IL-6, tumor necrosis factor alpha, and IFN-gamma were detected in the oral mucosae of both naïve and infected mice. The results indicate that recovery from oropharyngeal candidiasis in this model is dependent on CD4+-T-cell augmentation of monocyte and neutrophil functions exerted by Th1-type cytokines such as IL-12 and IFN-gamma.

FIG. 1

Oral infection after CD4⁺- and CD8⁺-T-cell depletion by monoclonal antibodies in BALB/c (A) and CBA/CaH (B) inbred mice. Bars represent scores (means ± standard errors of the means [SEM]) for a minimum of 10 mice/group. Control mice received no antibody. Systemic T-cell depletion did not significantly affect the severity of oral infection.

FIG. 2

Oral infection after CD4⁺- and CD8⁺-T-cell depletion in irradiated BALB/c mice. Irradiated mice were treated with 800 rads of γ-irradiation to the head and neck. Mice were depleted of either CD4⁺ or CD8⁺ T cells. Control mice received no antibody. Bars represent scores (means ± SEM) for a minimum of 10 mice/group. CD4⁺-T-cell depletion significantly prolonged the infection in irradiated mice compared to that in control mice (•, P < 0.01) and that in mice treated with anti-CD8 monoclonal antibody and irradiation (, P < 0.001). SEM were 0 if error bars are not shown.

FIG. 3

Oral infection after PMNL depletion in BALB/c (A) and CBA/CaH (B) mice. Test animals received monoclonal antibody injections prior to C. albicans infection and then at 48-h intervals until day 8. Control mice received no antibody. Bars represent scores (means ± SEM) for a minimum of 10 mice/group. Test mice were significantly different from control mice (, P < 0.05) using Dunnett's test of the ANOVA.

FIG. 4

Oral infection after macrophage inactivation in BALB/c (A) and CBA/CaH (B) mice. Test animals received carrageenan prior to C. albicans infection. Control mice received no treatment. Bars represent scores (means ± SEM) for a minimum of 10 mice/group. Test mice were significantly different from control mice (, P < 0.01) using Dunnett's test of the ANOVA.

FIG. 5

Oral infection after PMNL depletion and macrophage inactivation in BALB/c (A) and CBA/CaH (B) mice. Test animals received monoclonal antibody and carrageenan prior to C. albicans infection. Control mice received no treatment. Bars represent scores (means ± SEM) for a minimum of 10 mice/group. Test mice were significantly different from control mice (, P < 0.01) using Dunnett's test of the ANOVA.

FIG. 6

Histopathological sections of BALB/c (A) and CBA/CaH (B) oral tissue infected with 10⁸ C. albicans yeast cells following PMNL depletion and macrophage inactivation (day 4). Sections show abundant Candida hyphae penetrating the surface epithelium, with the absence of PMNL microabscesses. Sections were stained with periodic acid-Schiff stain. Scale bars, 45 μm.