Project A4

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

Project Description

Aspergillus fumigatus can cause two forms of pathogenesis: invasive aspergillosis (IA) in neutropenic patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with chronic obstructive lung disease as well as in immunosuppressed patients. While it is well known that these infections are accompanied by insufficient Th1 (IA) and overwhelming Th2 (ABPA) responses respectively, little is known about the impact of regulatory T cells (Treg) on the outcome of these infections. Recent studies using mouse models of experimental IA as well as studies on ABPA revealed that regulatory T cells (Treg) are required for the development and maintenance of a durable protective anti-fungal immunity, because these cells are able to prevent detrimental tissue damage and to restore homeostasis. In addition, our data suggest that Treg are, at least in part, bona fide induced during murine aspergillosis and therefore are specific for A. fumigatus antigens. Taken together, these studies indicate a crucial role for regulatory T cells in the counter-balancing of inflammatory anti-fungal immune responses during IA and ABPA. Therefore, it is most likely that insufficient Treg responses negatively affect the development of a protective immunity in patients suffering from IA and ABPA. Consequently, the development of strategies for Treg cell-based therapies would be beneficial to overcome uncontrolled A. fumigatus-mediated infections. In this project, we will determine the contribution of human Treg cells to the regulation of A. fumigatus-specific immune responses by comparing Treg differentiation and function in healthy human donors and patients suffering from IA and ABPA. On the basis of these data, we will develop strategies for Treg cell-based therapies by the generation of A. fumigatus-specific Treg cells for adoptive T cell transfer.

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

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
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
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

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 doi: 10.1038/leu.2017.41 [Epub ahead of print] PubMed