A Good Can of Worms: Helminth Infection Alone Can Drive Human-Like Cytokine Response in Laboratory Mouse Splenocytes

Abstract

The common preclinical mouse models lack the mature immune system of humans, making them poor models for clinical research. Commensal microbes and pathogens, through their co-evolutionary history with the mammalian immune system, can shift the mouse immune system toward that of humans. Using rewilding and Trichuris muris helminth infection, we examined the independent and combined effects of microbial exposure and infection on immune functions and phenotypes in C57BL/6J (B6) and B10.BR (B10) mice. For immune phenotypes, we found that rewilding shifted the mouse blood lymphocyte to neutrophil proportions toward those of humans, and that infection increased spleen mass in B6 mice only. For immune function, we measured Interferon-γ (IFN-γ) and Tumor Necrosis Factor (TNF-α) production by splenocytes stimulated in vitro with the CD28 superagonist (CD28SA) that caused life-threatening cytokine storms in humans but not in mice. Most notably, T. muris infection alone was sufficient to drive ~23-fold higher IFN-γ production to CD28SA stimulation, while rewilding alone drove a more modest ~4-fold increase, and the combined effect was the most dramatic at an ~111-fold increase. These results highlight the importance of environmental experience and host genotype as determinants of immune phenotype and function, and suggest that a single defined helminth infection may offer an accessible means to mature the mouse immune system for more accurate and safe clinical research.