# ApoB-specific CD4 T cells in mouse and human atherosclerosis

> **NIH NIH P01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2020 · $389,294

## Abstract

Project 4 description
Atherosclerosis is known to be controlled by regulatory T cells (Tregs), but neither the antigen specificity nor
the location nor the mechanism by which these cells protect are known. Project 4 is testing the hypothesis that
regulatory CD4 T cells express and secrete IL-10 in response to their cognate antigen, ApoB, the main core
protein of low density lipoprotein (LDL). This is based on the discovery of a significant number of ApoB-specific
CD4 T cells in mice and in humans, using mouse and human MHC-II tetramers and dextramers loaded with
mouse and human ApoB peptides, respectively. Specific Aim 1 is to test this hypothesis in mice by studying
atherosclerosis in Apoe-/- mice and following the natural history of the ApoB-specific CD4 T cell repertoire by
flow cytometry (FACS), mass cytometry (CyTOF) and RNA-Seq (through core E). To conclusively test whether
IL-10 from ApoB-specific CD4 T cells is required for atheroprotection, we will harvest ApoB-specific CD4 T
cells from Apoe-/- (IL-10 sufficient) or CD4CreIl10fl/flApoe-/- (IL-10-deficient) donors and separately transfer them
into recipient Apoe-/- Cd4-/- mice. We hypothesize that the IL-10 sufficient CD4 T cells will be atheroprotective
and the IL-10 deficient CD4 T cells will not. Specific Aim 2 is to translate the findings to humans, using frozen
PBMCs from the MESA cohort (core D) and the UVa cohort (core C). Preliminary data show that we can detect
human ApoB-specific CD4 T cells in frozen PBMCs from subjects with subclinical cardiovascular disease
(CVD). We propose to test their ability to express (by FACS) and secrete (by EliSpot) IL-10, assess their
phenotype by CyTOF and define their transcriptome by RNA-Seq (through core E). We have discovered 30
human ApoB peptides that bind many human MHC-II (DR) alleles and we estimate that we can interrogate
>85% of all samples using 17 different tetramers and dextramers. In collaboration with core D, we propose to
correlate the number and phenotype of ApoB-specific CD4 T cells with subclinical CVD as defined by coronary
calcium (CAC) scores and CAC score progression. Project 4 will collaborate with project 1 on antigen
presentation by monocytes and intravital microscopy, project 2 on the importance of LDL modifications and
project 3 on studying the B1 cell response to LDL. When the proposed work is completed, we will understand
the role of ApoB-specific CD4 T cells in modulating atherosclerosis by IL-10. The mechanistic mouse work
provides the basis for testing the relevance of ApoB-specific CD4 T cells in CVD patients. ApoB-specific CD4 T
cells are likely useful immunological biomarkers in atherosclerosis and the results can guide future therapeutic
and preventive efforts.

## Key facts

- **NIH application ID:** 9940778
- **Project number:** 5P01HL136275-04
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Klaus F. Ley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,294
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940778

## Citation

> US National Institutes of Health, RePORTER application 9940778, ApoB-specific CD4 T cells in mouse and human atherosclerosis (5P01HL136275-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9940778. Licensed CC0.

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