Cross-protective TH1 immunity against Aspergillus fumigatus and Candida albicans

Abstract

T cell-mediated heterologous immunity to different pathogens is promising for the development of immunotherapeutic strategies. Aspergillus fumigatus and Candida albicans, the 2 most common fungal pathogens causing severe infections in immunocompromised patients, are controlled by CD4 ؉ type 1 helper T (T H 1) cells in humans and mice, making induction of fungus-specific CD4 ؉ T H 1 immunity an appealing strategy for antifungal therapy. We identified an immunogenic epitope of the A fumigatus cell wall glucanase Crf1 that can be presented by 3 common major histocompatibility complex class II alleles and that induces memory CD4 ؉ T H 1 cells with a diverse T-cell receptor repertoire that is cross-reactive to C albicans. In BALB/c mice, the Crf1 protein also elicits cross-protection against lethal infection with C albicans that is mediated by the same epitope as in humans. These data illustrate the existence of T cell-based cross-protection for the 2 distantly related clinically relevant fungal pathogens that may foster the development of immunotherapeutic strategies. (Blood. 2011;117(22):5881-5891)

Induction of A. fumigatus-specific CD4-positive T cells in patients recovering from invasive aspergillosis

“…6 In healthy individuals the presence of Aspergillus-specific T cells in peripheral blood was demonstrated by stimulating peripheral blood mononuclear cells (PBMC) with Aspergillus crude extracts or conidia, A. fumigatus recombinant proteins or overlapping peptides of A. fumigatus proteins. 5,[7][8][9][10][11][12][13] We have previously identified Crf1-and Catalase1-specific T cells in healthy individuals using overlapping peptides. Crf1-and Catalase1-specific T cells recognizing a broad variety of T-cell epitopes were identified in the majority of healthy individuals and Aspergillus reactivity was shown by stimulating the T cells with Aspergillus protein extract or recombinant protein.…”

Immunotherapy for viral and fungal infections

“…21,28 New strategies of T-cell selection using antigen-induced T-cell stimulation and isolation by cytokine capture assay, streptamer technology 29 or via increased expression of activation markers has been developed. 9,10,30 In a recent study, this approach has been successfully applied to patients with chemorefractory CMV infection and disease. 31 Adoptive transfer of antigen-specific T cells for EBV, ADV and CMV is now established at several centers in a clinical protocol with the required clinical, immunological, virological, technical and regulatory preconditions.…”

“…An alternative technology developed in our labs is the selection of T cells directed against viral and fungal antigenic epitopes by stimulation with peptide mixes covering several relevant CMV-, EBV-, ADV-, Aspergillus fumigatus-and Candida albicans-specific T-cell epitopes followed by selection via the upregulated activation markers (for example, CD137, CD154 and so on). 9 For generation from multipathogen-specific T cells from a seronegative donor in vitro priming using professional APCs pulsed with the relevant peptides from immunodominant viral antigens in the presence of exogenous cytokines, especially IL7 and IL15 can be used. In addition, the depletion of regulatory T cells and the selection of the primed pathogen-specific T cells via surface expression of activation markers plus/without in vitro expansion have been shown to further increase the yield of multipathogen-specific T cells.…”

Immunotherapy for opportunistic infections: Current status and future perspectives

“…If DCs can be used in accordance to GMP, it might help to further expand specific T cells. 83 Perrucio et al conducted a study using expanded Aspergillus-specific T cells after haploidentical transplantation in patients with a history of IA. 84 In this study, control transplant recipients who did not receive such adoptive transfer tended to suffer from IA and had no detectable reconstitution of Aspergillus-specific T cells after transplantation.…”