# Immune Surveillance of Antigen Processing Pathway

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $558,198

## Abstract

Project summary
 The long term goal of our research is to understand and manipulate immune surveillance pathways. The
antigen processing pathway yields thousands of peptide/MHC complexes (pMHC I) on the cell surface as
potential ligands for CD8+ T cells to allow detection of viruses or cancer. It is now clear that generation of the
normal pMHC I repertoire requires peptide trimming in the endoplasmic reticulum (ER) by ERAAP, the ER
aminopeptidase associated with antigen processing. The ERAAP is targeted for immune evasion by viruses
and polymorphisms in this gene are linked to many autoimmune diseases. It is therefore essential to monitor
ERAAP activity to ensure effective immune surveillance by CD8+ T cells.
 We had discovered earlier that the unique FL9 nona peptide — derived from the Fam49a/b proteins of
unknown function — was presented by the non-classical MHC Ib molecule called Qa-1b only in ERAAP-
deficient cells. This FL9 peptide/Qa-1 complex, called QFL was recognized by QFL-specific CD8+ T cells which
lysed target cells expressing this ligand. Thus QFL- T cells are a mechanism for detecting and eliminating cells
with ERAAP-deficiency. The QFL-T cells are relatively abundant, and share key characteristics with other
innate-like iNKT (invariant NK T) and MAIT (mucosal - associated invariant T) cells which are also restricted by
non-classical MHC Ib molecules and respond to various microbial and self-antigens.
 Here we propose to fill gaps in our understanding of how the immune system monitors the fidelity of
antigen processing in the ER. We hypothesize that QFL-specific CD8+ T cells and the mechanisms for
generating the QFL-ligand are conserved sensors for detecting ERAAP-inhibition. Furthermore, disruption of
these mechanisms in ERAAP-deficient mice may result in autoimmune obesity.
 We will accomplish these goals by (a) characterizing the αβ TCRs and the thymic developmental pathway
for QFL-T cells to understand how these cells arise and acquire their unique functions, (b) defining the
molecular steps for generating the QFL-ligand by analyzing the processing of Fam49a/b precursors into the
FL9 peptide for loading the Qa-1 MHC Ib, and (c) defining the anatomical location(s) and function(s) of QFL-T
cells in normal WT mice as well as their obese ERAAP-/- counterparts.
Relevance
Autoimmunity results when immune tolerance to self-antigens is disrupted. Understanding how self-antigens
are produced by proteolytic enzymes will likely reveal potential ways to intervene in autoimmune disorders.

## Key facts

- **NIH application ID:** 10112811
- **Project number:** 5R01AI130210-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Scheherazade Sadegh-Nasseri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,198
- **Award type:** 5
- **Project period:** 2017-03-08 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112811

## Citation

> US National Institutes of Health, RePORTER application 10112811, Immune Surveillance of Antigen Processing Pathway (5R01AI130210-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112811. Licensed CC0.

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