Regulatory function of CD160 in helminth infection

• Applicant: Professorin Dr. Minka Breloer
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521628293

Helminth parasites infect every 4th human and have evolved sophisticated mechanisms to downmodulate their host`s immune system to prolong their survival. We reported previously that the parasitic nematode Strongyloides ratti delayed its immune-driven ejection from the intestine via the induction of regulatory T cells and via the upregulation of the regulatory receptor B and T lymphocyte attenuator (BTLA) on effector T cells. BTLA is part of a complex network of several regulatory receptors that bind to their ubiquitously expressed ligand Herpes Virus Entry mediator (HVEM). This application aims at elucidating the role of the alternative HVEM ligand CD160 in regulating immunity to helminths. Our research question is based on a preliminary screen of S. ratti parasite burden in mice deficient for several HVEM ligands including a newly generated CD160 ko mouse strain. To our surprise, we observed reduced intestinal parasite burden in mice lacking CD160 at early time points of infection and, in the absence of adaptive immunity, reciprocally increased parasite burden at later time points of infection. Thus, we propose that CD160-mediated signals display dual and opposing functions during intestinal helminth infection. CD160 is expressed on T and NKT cells. For innate cells, CD160 expression was described for NK cells and for innate intraepithelial intestinal cell populations, such as innate lymphoid cells and mast cells. These cells also contribute to anti-S. ratti immunity. Within this research project we will first perform a thorough characterisation of the different innate CD160-expressing cell populations in S. ratti-infected mice using multicolour flow cytometry and single cell sequencing. While CD160 is a positive regulator of NK cells, the consequences of CD160-engangement on other cell types appear to be context-dependent. We intend to compare the immune response CD160-competent and CD160-deficient mice to define immune pathways that are changed in the absence of CD160. We will focus on early time points when CD160 antagonizes S. ratti ejection from the intestine and late time points when CD160 promotes innate anti-S. ratti immunity. Comparing the function of the relevant WT and CD160 ko innate immune cells (mast cells, innate lymphoid cells, NK cells) in vitro and in vivo, we will provide a causal link between the cell populations that express CD160 during S. ratti infection and the immune pathways changed in the absence of CD160. As the CD160-ligand HVEM is also a (positive) signalling receptor we finally intend to distinguish between signals delivered into the CD160-expressing and signals delivered into the HVEM-expressing cell. In summary, we expect to elucidate in great depth the precise mechanism of action of CD160-HVEM-mediated regulation of anti-helminth immunity in the intestine and thereby our study will shed further light on the function of this network in general.

• DFG Programme: Research Grants