Extensive MHC class I-restricted CD8 T lymphocyte responses against various yeast genera in humans

Abstract

The human cellular immune response against 14 distantly related yeast species was analyzed by intracellular cytokine staining of lymphocytes after ex vivo stimulation of whole blood. While the CD4 T cell response was marginal, extensive MHC class I-restricted CD8 T cell responses were detected against a number of species including spoiling, environmental and human pathogenic yeasts. The yeast-specific CD8 T cells expressed interferon-gamma but lacked expression of CD27 and CCR7, indicating that they were end-differentiated effector memory cells. Mainly intact yeast cells rather than spheroplasts were able to induce cytokine expression in T cells demonstrating that the dominant immunogens were located in the yeast cell wall. Together these data underline the importance of the cellular immune response in protecting humans against yeast and fungal infections. And, from another perspective, recombinant yeast suggests itself as a potential vaccine candidate to efficiently induce antigen-specific CD8 T cell responses.

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

“…H. capsulatum infection leads to cross-presentation and a protective CD8 + T cell response in mice [53]. Furthermore, CD8 + T cell responses specific for various types of yeast are detected in humans [54]. This clearly indicates that crosspresentation of fungi results in the activation of CD8 + T cells in vivo.…”

Delivery of functional DNA and messenger RNA to mammalian phagocytic cells by recombinant yeast

“…A simple rupture of the phagolysosomes seems unlikely as such an event would release lysosomal activity, which, as a consequence, would presumably affect the viability of the APCs. However, there are several reports in which proteins delivered by recombinant yeast are capable of entering in particular the MHC I pathway via crosspresentation, 11,12,18,20,32 a mechanism whose molecular basis is currently controversially discussed. One explanation for this phenomenon could be the observation that phagosomes containing exogenous proteins merge with the endoplasmic reticulum (ER) in professional APCs, such as macrophages and DCs.…”

“…9,10 Yeast has been repeatedly shown to generate adaptive (including cell-mediated) immune responses in mice [11][12][13][14][15][16][17][18][19] and also in humans. 20 In contrast to the majority of attenuated bacteria and mammalian viruses (which are already under investigation as DNA/RNA carriers, for example, Listeria), several yeast genera possess the GRAS ('generally regarded as safe') status, which would facilitate the approval of a yeast-based vaccine considerably. It is devoid of endotoxins and super antigens, and most strains are, due to the tremendous experience in using yeast in genetics and biotechnology for many years, accessible to genetic modifications allowing among others the development of multivalent vaccines and/or the modulation of immune responses.…”

Human yeast-specific CD8 T lymphocytes show a nonclassical effector molecule profile

“…Additional cultivation in human serum at 37°C for 6 h was sufficient to induce a switch to the filamentous growth form which was visualized by light microscopy. For the stimulation assay, C. albicans and C. tropicalis were used in the filamentous form, because the respective single cells are less immunogenic [19]. Before adding to the whole blood, yeasts were washed three times in PBS (3,000 rpm, 10 min, RT).…”

“…In addition to CD4 T cells, CD8 T cells are important and necessary to finally restrict the infection [9,16]. Consistently, healthy humans show extensive frequencies of MHC-I-restricted CD8 T lymphocytes against various yeast genera [19] but the role of these yeast-specific CD8 T lymphocytes in defense against the fungal pathogens is inadequately characterized.…”