Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection

Marion Rolot,Olivier Denis,Alain Vanderplasschen,Alisha Chetty,Xue Xiao,Rick M Maizels,William G C Horsnell,Laurent Gillet,Annette M Dougall,Bénédicte Machiels,Cornelis Hokke,Frank Brombacher,Justine Javaux,Ting Chen,Benjamin G Dewals,Murray E Selkirk

doi:10.1038/s41467-018-06978-5

Abstract

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44hiCD62LhiCXCR3hiCD49dlo TVM cells through direct IL-4 signaling in CD8+ T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8+ T cells, leading to a subsequently raised antigen-specific CD8+ T cell activation that enhances control of viral infection.

Highlights

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes
To investigate how the TVM cellular compartment is affected by helminth-induced inflammation, we first used a wellcharacterized experimental model for inducing type 2 inflammation by helminth Ags, in which eggs of the trematode parasite S. mansoni are injected intraperitoneally (i.p.) to 6–8-week-old female BALB/c mice before intravenous challenge (i.v.) 2 weeks later, and responses measured at d22 after the first injection (Supplementary Figure 1a)[27]
IL-4 and IFN-γ are usually considered antagonistic as hallmark cytokines of type 2 and type 1 immunity, respectively

Summary

Introduction

Infection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4) This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. Conditioning of T cells can impart memory-like properties and functions in absence of encounter of their cognate Ag13, and be important for priming CD4+ T cells for subsequent type 2 immunity[14] This is the case for CD8+ T cells; bystander or virtual memory CD8+ T cells (TVM) emerge from early in life in naive mice[15,16,17,18] and humans[19,20] in the absence of specific Ag stimulation and are Ag-inexperienced. Whereas TVM development in C57BL/6 mice mostly depends on IL-15, IL-4 is the main driver of TVM expansion in BALB/c mice[25]

Methods

Results

Conclusion