Resistance to Cryptococcus neoformans infection in the absence of CD4 + T cells

Abstract

Previous studies of Cryptococcus neoformans infection have revealed a role for CD4+ T cells and CD8+ T cells in anticryptococcal resistance in the lungs, but such a role has been revealed only for CD4+ T cells in the brains of experimentally infected mice. In this study, we found that mice genetically engineered to lack CD4+ T cells could be successfully vaccinated to express resistance to a rechallenge with Cryptococcus neoformans, provided the challenge dose was kept to lower than 1000 organisms per mouse. The challenge infection was uniformly lethal for unvaccinated control mice. Depletion of CD8+ T cells weakened this resistance to re-challenge: both naïve and vaccinated mice that were treated with antibody raised against CD8+ T cells died significantly earlier than did mice that received an irrelevant control antibody. In vitro, purified CD8+ T cells taken from draining lymph nodes of antigen-experienced mice were less efficient than were identically prepared CD4+ T cells at stimulating the cells of a transformed microglial cell line to inhibit C. neoformans proliferation, possibly mirroring the inferiority of CD8+ T-cell-mediated protection observed in vivo. RNase protection assays showed similar IFN-gamma mRNA levels in both lymphocyte subsets. Class II major histocompatibility antigen expression was up-regulated strikingly on microglia cultured with IFN-gamma, but class I expression was less dramatically affected. Therefore microglial cell interaction may be more greatly enhanced with CD4+ cells than with CD8+ cells.

Inheritance of Immune Polarization Patterns Is Linked to Resistance versus Susceptibility toCryptococcus neoformansin a Mouse Model

“…ϩ cells can play a supportive role in generation of a Th1 milieu in the lungs and benefit cryptococcal clearance (1,25,27,37). Thus, the increased numbers of CD8 ϩ cells could contribute to the gradual shift toward a Th1 phenotype in F1 mice and/or contribute to the improved clearance after week 3 postinfection.…”

Role of microglia in fungal infections of the central nervous system

“…Additionally, the phagocytic function of microglia reduces C. neoformans growth and increases expression of MHC II in the presence of CD4 C cells using murine cell lines. 72 In another study, alongside IL-12, the addition of IL-23p19 enhances the microglial response to C. neoformans. 73 Differences in response to NO by animal models have been observed.…”

Protection from Direct Cerebral Cryptococcus Infection by Interferon-γ-Dependent Activation of Microglial Cells

“…IFN-␥ has been demonstrated to enhance the anticryptococcal activity of murine microglial cells in vitro by inducing MHC class II expression and NO production (37)(38)(39). To determine whether IFN-␥ was an important mediator of anti-CD40 and IL-2 immunotherapy in the brain, the efficacy of anti-CD40/IL-2 treatment in IFN-␥ KO (GKO) mice were compared with WT mice.…”