Proof of long-term immunological memory in cartilaginous fishes

Organized B cell sites in cartilaginous fishes reveal the evolutionary foundation of germinal centers

“…Prior to this study, the reported absence of GCs, 44 , 45 or potentially analogous structures, 46 in cartilaginous fishes lay at odds with accumulating data showing that sharks can produce robust antigen-specific responses following immunization, affinity mature their B cell repertoires, and maintain immunological memory for many years. 7 – 9 Here, we demonstrate that cartilaginous fishes and, by inference, the common jawed vertebrate ancestor possess(ed) many of the fundamental components for B cell selection as are found in the GCs of endothermic vertebrates, specifically (1) populations of AID-expressing, CXCR4 + centroblast-like, and CXCR5-high centrocyte-like B cells; (2) cells with functional similarity to mammalian Tfh cells that express many genes with roles in co-stimulation and B cell clonal selection; (3) professional APCs possessing some mechanism for presenting non-degraded antigen, thus permitting the selection of BCRs against multiple epitopes; and (4) evidence of CDR-biased mutation following AID-mediated SHM of Ig genes. Combined, our data suggest that shark B cell clones compete for antigen binding and co-stimulatory signals from Tfh-like cells in the center of the follicle before migrating in a CXCR4-directed fashion to the periphery of the follicle to proliferate and mutate their receptors.…”

“… 7 , 8 Durable immunological memory has also been confirmed in this species. 7 , 9 These findings raise the question of how sharks select antigen-specific B cell clones and affinity mature their Ig repertoires in the absence of GCs. To investigate this paradox, we performed RNA sequencing on single nuclei (snRNA-seq) from the nurse shark spleen, allowing us to characterize the cell types present, and RNAscope to provide in situ cellular resolution of key marker gene expression, following immunization with the fluorescent protein R-phycoerythrin (PE).…”

450 million years in the making: mapping the evolutionary foundations of germinal centers

“…Shark Ig genes mutate at very high rates ( 26 , 129 ), and both mIgM and IgNAR undergo affinity maturation ( 17 , 21 ). Humoral immunological memory has been described in nurse shark up to 8 years after primary exposure ( 31 ).…”

“…Finally, there is evidence for secondary recall responses in ectothermic jawed vertebrates ( 21 , 28 – 30 ), indicative of B cell memory (although recall titers do not always exceed those of the primary response). Indeed, in some taxa immunological memory has been shown to persist for significant periods (>8 years) after primary exposure ( 31 ). Together these results demonstrate that ectothermic jawed vertebrate B cell responses are functionally protective in the absence of true GCs, even if affinity maturation is not as robust.…”

Putative Immunological Functions of Inducible Skin-Associated Lymphoid Tissue in the Context of Mucosa-Associated Lymphoid Tissue

“…However, they already possess an acquired immune system with many basic cellular and molecular similarities to those of mammals. The spleen has already been described as a SLO in sharks, and it possesses organized lymphoid tissue, albeit no germinal center ( 39 ). Sharks have aggregates of GALT in spiral valves, which are structures that increase the intestinal wall surface area due to their extra folds and twists ( 40 , 41 ).…”