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

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.

Similar but different: virtual memory CD8 T cells as a memory‐like cell population

“…12,14,15 Given the pivotal role of IL-15 in T VM -cell generation, high expression of IL-15Rb and Eomes can be used as additional phenotypic markers of T VM cells. 12 While nonredundant roles in T VM -cell generation are not observed for other common-gamma chain (cc) cytokines, IL-4 signaling can expand T VM -cell populations 1,12,16,17 and T VM cells express and maintain high levels of the IL-7a chain (CD127), 13 which is consistent with a role in their survival.…”

“…T VM cells bridge the gap between innate and adaptive immunity, providing both innate‐like and memory‐like functionality during this period of immunological vulnerability. Indeed, T VM cells are crucial for generation of rapid protective immunity in vivo in a number of bacterial and viral models . T VM cells are therefore proposed to provide an additional layer of heterogeneity within naïve CD8 T‐cell populations, ensuring that antigen‐naïve CD8 T cells are intrinsically diverse with regard to both (1) antigen specificity based on TCR expression and (2) preprogrammed response kinetics and functionality based on their IL‐15‐driven differentiation state …”

“…IL‐4 signaling also augments T VM ‐cell generation and may positively regulate IL‐15 signaling. Ablation of IL‐4 or its receptor leads to a modest decrease in the frequency of T VM cells, while IL‐4 production during helminth infection increases the frequency of T VM cells . In addition, the development of a population of T MP cells, known as innate memory CD8 T (T IM ) cells is dependent on IL‐4 but not IL‐15 (Table ) (reviewed in).…”

“…While the cumulative impact of multiple infections on T VM ‐cell homeostasis has not been defined, it is well established that viral infections can cause expansion of T MP and presumably T VM cells . In addition, a single infection with helminths was sufficient to increase T VM ‐cell frequency in the periphery, in an IL‐4 dependent manner, leading to more effective clearance of subsequent murid gammaherpesvirus 4 infection or listerial infection . This illustrates that pathogenic exposures have a significant acute impact on T VM ‐cell homeostasis and function but the long‐term impact of such exposures remains to be characterized.…”

IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection

“…Because IL-4/IL-13 or M2a polarization is shown to play a clear role in other disease states and is likely to be relevant to a variety of helminth-infected African patient populations exposed to EBOV [55], we focused here on the effect of M2a polarization on rVSV/EBOV GP infection. While a large number of studies have used IL-4 and IL-13 to elicit the M2a phenotype in macrophages [31,56,57], we verified in our primary cells of interest, murine resident peritoneal macrophages (pmacs), that changes in gene expression occurred that were reflective of functional macrophage polarization following IL-4/-13 treatment.…”