# Evolution of Adaptive Immunity

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $386,250

## Abstract

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.

## Key facts

- **NIH application ID:** 9899205
- **Project number:** 5R01AI140326-27
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Martin F Flajnik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2013-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899205

## Citation

> US National Institutes of Health, RePORTER application 9899205, Evolution of Adaptive Immunity (5R01AI140326-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899205. Licensed CC0.

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