# Repertoire selection of AQP4-specific T cells that cause CNS autoimmunedisease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $447,478

## Abstract

PROJECT SUMMARY / ABSTRACT
 Based upon the observation that aquaporin-4 (AQP4)-specific antibodies are IgG1, a T cell-dependent isotype, it was
hypothesized that aquaporin-4 (AQP4)-specific T cells have a key role in neuromyelitis optica (NMO) pathogenesis.
AQP4-specific T cells have been identified in NMO patients and, in comparison to healthy controls (HC), AQP4-reactive
T cells are expanded and exhibit Th17 polarization, findings that further support the role of Th17 cells in NMO.
Unfortunately, it is not feasible to evaluate how AQP4-reactive T cells participate directly in CNS inflammation in NMO
patients. Thus, it is important to develop models to evaluate the potential role of AQP4-specific T cells in NMO.
 Initial attempts in generating an in vivo AQP4-based NMO model in wild-type (WT) mice and rats have not met with
success. Recently, it was observed that pathogenic AQP4-specific T cells exist in AQP4-deficient (AQP4-/-) mice. Those T
cells recognize two novel determinants. In comparison to other AQP4 determinants identified in WT mice, the novel
determinants induce robust proliferation in AQP4-/- mice, but only a weak response in WT mice. Hyper-reactivity is
AQP4-specific, but not epitope-specific as we discovered a second AQP4 epitope induced vigorous proliferation in AQP4-
/-, but not WT, mice. The T cell receptor (TCR) repertoires used for recognition of these determinants in AQP4-/- and WT
mice are distinct. T cells reactive to these determinants isolated from AQP4-/- donor mice induced clinical and histologic
CNS autoimmune disease in 100% of recipient WT mice tested. Collectively, these findings represent the first successful
induction of clinical AQP4-targeted CNS autoimmunity. Our findings suggest responses to those epitopes in AQP4-/- mice
reflect a loss of central T cell tolerance. Findings from studying mice deficient in T cells only or B cells only indicate that
peripheral T cell regulation also alters expression of pathogenic AQP4-specific T cells.
 We propose to test our hypothesis that there is a defect in thymic negative selection of AQP4-specific T cells in mice,
a possibility that may be relevant to NMO pathogenesis. We will examine how peripheral T cell regulation may influence
pathogenic AQP4-specific immune responses. In Specific Aim 1, by using unique approaches and novel mice, we will
characterize the phenotype of pathogenic AQP4-specific T cells and generate AQP4-specific TCR transgenic mice. In
Specific Aim 2, we will characterize the repertoire of AQP4-specific T cells in AQP4-/- and WT mice that express HLA-
DR17 (DRB1*0301), the MHC II allele most highly associated with NMO. Separately, we will examine AQP4-specific T
cell responses in NMO patients to determine if DR17-restricted AQP4-specific T cell epitopes identified those mice
correspond to AQP4 T cell epitopes in NMO patients. In preliminary data, using these mice we discovered a novel HLA-
DR17-restricted AQP4 determinant, and observed that it is recogn...

## Key facts

- **NIH application ID:** 9841899
- **Project number:** 5R01AI131624-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** SCOTT S ZAMVIL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,478
- **Award type:** 5
- **Project period:** 2018-12-24 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841899

## Citation

> US National Institutes of Health, RePORTER application 9841899, Repertoire selection of AQP4-specific T cells that cause CNS autoimmunedisease (5R01AI131624-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841899. Licensed CC0.

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