Project A4

Impact of regulatory T cells on human infections caused by Aspergillus fumigatus

Aspergillus fumigatus can cause invasive Aspergillosis (IA) with insufficient Th1 and allergic bronchopulmonary Aspergillosis (ABPA) with an overwhelming Th2 response. The beneficial modulation of regulatory T cells (Tregs) and their impact on these diseases are not well understood. Therefore we collected in collaboration with A1 and A2 samples of post allo-HSCT patients with proven or probable A. fumigatus infection and without IA. Through Next Generation Sequencing we identified four single nucleotide variants in Treg genes that will be validated for diagnostic approaches as our first aim.

Our second aim is the development of an adoptive T cell therapy for A. fumigatus infections. For that purpose, we have genetically engineered CD4 T cells and Tregs to express T cell receptors (TCR) that are highly specific for the A. fumigatus cell wall glucanase Crf1. In vitro analysis of these Crf1-TCR expressing CD4 T-cells and Tregs showed cell-specific immunofunctional responses (activation, cytokine release, proliferation) towards peptide-pulsed dendritic cells as well as to naturally processed and presented A. fumigatus antigens. Furthermore, genetically engineered Crf1-TCR Tregs successfully suppressed antigen-specific cytokine release and proliferation of Crf1-specific CD4 T-cells in a concentration dependent manner. This promising anti-A. fumigatus response will be further analyzed in in vivo IA and ABPA infection models to establish the approach of adoptive T-cell transfer therapy. To achieve appropriate pairing of the transferred TCRs, the Crf1-TCR will be further genetically optimized for efficient anti-Aspergillus T cell function and reduced risk of an unspecific T cell response. Additionally, we will design TCRs with novel antigen specificities to further strengthen the anti-Aspergillus response.

Principal Investigator
Prof. Dr. Max S. Topp
Prof. Dr. Max S. Topp

Faculty of Medicine, Department of Internal Medicine II and Research Center for Infectious Diseases (ZINF)  

Julius Maximilians University Würzburg

topp_m@klinik.uni-wuerzburg.de

Publications
Author Year Title Journal Links
Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, Rasche L, Hartmann E, Dandekar T, Einsele H, Topp M 2017 Frequency of regulatory T cells determines the outcome of the T cell engaging antibody blinatumomab in patients with B precursor ALL. Leukemia 31: 2181-90 PubMed
Hellmann AM, Lother J, Wurster S, Lutz MB, Schmitt AL, Morton CO, Eyrich M, Czakai K, Einsele H, Loeffler  2017 Human and murine innate immune cell populations display common and distinct response patterns during their in vitro interaction with the pathogenic mould Aspergillus fumigatus. Front Immunol 8: 1716 PubMed
Berges C, Kerkau T, Werner S, Wolf N, Winter N, Hünig T, Einsele H, Topp MS, Beyersdorf N 2016 Hsp90 inhibition ameliorates CD4+ T cell-mediated acute graft versus host disease in mice. Immun Inflamm Dis 4: 463-73 PubMed
Stuehler C, Nowakowska J, Bernardini C, Topp MS, Battegay M, Passweg J, Khanna N 2015 Multispecific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections. J Infectious Dis 211: 1251-61 PubMed
Bedke T, Iannitti RG, De Luca A, Giovannini G, Fallarino F, Berges C, Latgé JP, Einsele H, Romani L, Topp MS 2014 Distinct and complementary roles for Aspergillus fumigatus-specific Tr1 and Foxp3+ regulatory T cells in humans and mice. Immunol Cell Biol 92: 659-70 PubMed