Standing on the shoulders of mice

Abstract

While inbred mice have informed most of what we know about the immune system in the modern era, they have clear limitations with respect to their ability to be informative regarding genetic heterogeneity or microbial influences. They have also not been very predictive as models of human disease or vaccination results. Although there are concerted attempts to compensate for these flaws, the rapid rise of human studies, driven by both technical and conceptual advances, promises to fill in these gaps, as well as provide direct information about human diseases and vaccination responses. Work on human immunity has already provided important additional perspectives on basic immunology such as the importance of clonal deletion to self-tolerance, and while many challenges remain, it seems inevitable that "the human model" will continue to inform us about the immune system and even allow for the discovery of new mechanisms.

Keywords: collaborative cross mice; human immunology; humanized mice; inbred mice; organoids.

Figure 1.. A comparison of mouse and human skin (Zomer and Trentin, 2018).

Human skin is much thicker and is more complex than mouse skin. In their immune composition they differ in their epidermal layer, where mice have the unique DETC cells with their uniform γδ T cell T cell receptors, and share with humans Langerhans and CD8 T cells(Pasparakis et al., 2014). Adapted with permissionfrom Nature (Pasparakis el al., 2014) copyright 2014.

Figure 2.. Mouse and human splenic immune cellular architecture at steady state.

There are structural differences between the murine (left) and human (right) splenic immune system, most notably, the organizationof T cell zone (TC, turquoise; also known as PALS) and B cell zone (BCZ) follicles (gray and shades of blue, shown with light zone, LZ, and dark zone, DZ, organization in mouse spleen) within the WP and the border between the WP and RP, the MZ (marginal zone) in mouse or perifollicular zone (PFZ) in human (dark blue outer ring). Because applications of advanced imaging techniques to the human spleen have been limited, the extent to which the mouse MZ and human PFZ are analogous remains unknown. For example, the precise layering and composition of macrophage subsets in the MZ is known for mice (see bottom left box) CD169+ MMMs (dark blue) form a concentric ring around the WP with MZMs (light blue) and MB cells(darker blue)-but not for humans. In humans, MZB cells surround activated B cells, containing a GC (light blue in the human spleen on the right) and Corona (gray,”Cor”). The homeostatic location of dendritic cell (DC) subsets in mice is shown (with cDC2s in the bridging channel, BC, and cDC1s in the TCZ, MZ and RP, red pulp). Release of blood into the MZ of the WP from a central arteriole (CA) is shown. From, Science Immunology (Lewis et al., 2019). Adapted with permission from AAAS.