# Molecular mechanisms of allorecognition in a basal chordate

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2020 · $290,117

## Abstract

When an immune cell interacts with a target cell, and receptors bind their cognate ligands, a
decision is made to react or not. Our long-range goal is to understand the basis of that decision.
How does a cell monitor events at the cell surface? What gets counted, and how are multiple
stimulatory and inhibitory signals integrated? How is that compared to a threshold value, and
during development and education processes, how does a cell know what the threshold is? And
once set, can these thresholds be manipulated? Each of these questions has major biomedical
significance, from understanding the changes in reactivity that lead to autoimmunity, to inducing
tolerance to a transplanted tissue.
We have the ability to study how these processes work during a single immune interaction. Our
model is histocompatibility in the basal chordate Botryllus schlosseri. Allorecognition in Botryllus is
controlled by a single locus (called the fuhc) with the following rules: individuals that share one or
both alleles are compatible; while those that share none are incompatible. Discrimination is based
on the detection of a self-allele, and the specificity of this system is significant: there are ca. 1000
fuhc alleles world-wide, thus the effector system can pick out a self-allele from a sea of competing
specificities. However, Botryllus does not have any recombination or somatic hypermutation
machinery, and this specificity relies on germline-encoded receptors.
This proposal is focused on understanding the biochemical mechanisms that underlie this innate
allorecognition specificity. The unique properties of Botryllus allorecognition make it an ideal model
for these studies: a single locus that determines outcome, the reaction occurs outside the body
between epithelial cells on the tips of macroscopic blood vessel, called ampullae, and the outcome
is determined by the integration of signaling pathways from only two receptors, one activating, and
one inhibitory, both of which can be manipulated in vivo. In Aim 1, we will use a novel fluorescent
labeling technique recently developed in our lab to isolate single ampullae cells and directly assess
the basis of specificity. Our working hypothesis is that this is due to genotype-specific alternative
splicing of a receptor called fester, and that will be directly tested here. Using this technique, we
have also found that ampullae are bifunctional and can reversibly de-differentiate into vascular
cells, which do not express allorecognition proteins, allowing us to characterize reversible changes
in candidate protein expression/alternative splicing, which will reveal the basis of specificity. In Aim
2, we will assess extracellular ligand/receptor interactions in vivo and in vitro. We will test putative
intracellular interactions between receptors and fuhc-encoded chaperones and scaffolding proteins
that may play a role in creating receptor complexes and contribute to specificity. In Aim 3, we will
characterize the signal transd...

## Key facts

- **NIH application ID:** 9836862
- **Project number:** 5R01GM123267-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Anthony W De Tomaso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $290,117
- **Award type:** 5
- **Project period:** 2017-03-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836862

## Citation

> US National Institutes of Health, RePORTER application 9836862, Molecular mechanisms of allorecognition in a basal chordate (5R01GM123267-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836862. Licensed CC0.

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