Sunday, February 2, 2025
2/2/2025
SUMMARY Studies of nonmammalian vertebrates (fish, amphibians, reptiles, and birds) have provided essential discoveries in adaptive immunity, especially regarding lymphocyte lineages, origins of the major histocompatibility complex (MHC), mucosal immunity, and antigen receptors. From work that we have done in sharks, the oldest living vertebrates with immunoglobulins, T cell receptors and the MHC, we hypothesize that the mammalian B1 cell paradigm is operable in neonatal and young animals. Sharks also have antibodies with invariant binding sites (germline- joined gene-encoded antibodies), which are expressed in secretory B cells but not in naïve B cells. The antibody is modeled to have an unusual binding site, it binds to self tissues and bacteria, and it is proposed to be a model for B1-derived antibodies in mammals. A second wave of shark B cells with a unique immunoglobulin repertoire (also B1-like, with little N-region addition) forms the nascent splenic white pulp, also proposed to be the paradigm for all vertebrates, which we will test in mice and amphibians. Regarding humoral immune responses, it is well known that nonmammalian vertebrates have poor affinity maturation of the antibody response and seem to lack follicular dendritic cells (FDC); thus the mechanism of how native antigen is presented to B cells is poorly understood. We have re-identified an antigen presenting cell (APC) in frogs that expresses high levels of MHC class II, and yet presents native antigen on its surface in the center of B cell follicles relatively late after immunization. We hypothesize that these APC perform a `double-duty,' presenting antigen to both T cells and B cells. Our data suggest that T cells are stimulated by these APC early in a response, and then the activated T cells license the APC to stop degrading antigen, upregulate B cell chemokines (cxcl13), and enter the follicle to present antigen to specific B cells. We hypothesize that this cell represents the paradigm for humoral responses in cold-blooded vertebrates, and that conventional mammalian DC can take on this `double-duty' phenotype in particular immune responses.
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