# Two MHCs versus one and the affect on T cell repertoire in autoimmune diabetes

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2021 · $33,983

## Abstract

PROJECT SUMMARY
Type 1 Diabetes (T1D) is strongly associated with the human MHC-II alleles HLA-DQ2 and HLA-DQ8.
In mouse models bearing the MHC-II allele I-Ag7
diabetes
protection.
MHC-II
diabetes.
restricted
MHC
parent.
TCR
disease
repertoire
of
and
method
workflows
cells
performed
sponsor
John
interdisciplinary
committee
also
at
application
of
outstanding
80 – 90% of female mice spontaneously develop autoimmune
within 6 months. While certain promote disease susceptibility, others provide
In humans, the HLA allele HLA-DQ6 provides protection, while in mice there are several alleles of
which, if co-expressed with the disease promoting allele radically reduce incidence of autoimmune
We have recently investigated how inheritance of two MHC alleles versus one affect T cells with a
T cell receptor (TCR) repertoire. Our preliminary evidence suggests that mice which inherit a second
allele have a dramatic decrease in TCR repertoire diversity and lack many unique TCRs present in either
We suspect that MHC-heterozygosity in diabetes-resistant mice leads to substantial gaps in the naïve
repertoire which reduces the numbers of autoreactive CD4 + T cells, thus contributing to reduction in
risk. This proposal is designed to test whether this is so, in mice expressing a restricted TCR
and in normal NOD T1D susceptible mice. The proposed study is expected to yield results capable
explaining how the most informative genetic risk factors to T1D (MHCII alleles) shape the T cell repertoire
may inform future intervention studies in individuals at risk for developing T1D. I propose the use of a new
to pair and sequence TCR α /β chains at much larger scales than currently possible, bioinformatic
to compare TCR repertoires and the development of retrogenic mice to validate that pathogenic T
are selectively absent from mice afforded protection against autoimmune diabetes. All experiments will be
at National Jewish Health, a leader in immunological research, under the guidance of my primary
and department chair Philippa Marrack, PhD, FRS. Remaining members of my sponsor team are Prof.
Kappler at National Jewish Health, and Prof. Victor Greiff at University of Oslo who will support my
training in diabetes and bioinformatics respectively. Moreover, I will consult with my thesis
and collaborators for support and guidance in performing these studies. My training program will
be supplemented by courses, journal clubs and presentations held through the Immunology PhD program
University of Colorado, Denver. Overall, the proposed project and training objectives in this F31 award
are devised to train me as a resourceful independent graduate student with a strong understanding
how to leverage bioinformatics, new RNA sequencing methods and basic science skills to address
questions in autoimmunity.
MHC-II molecules

## Key facts

- **NIH application ID:** 10312642
- **Project number:** 1F31DK130278-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Alexander J Brown
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,983
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312642

## Citation

> US National Institutes of Health, RePORTER application 10312642, Two MHCs versus one and the affect on T cell repertoire in autoimmune diabetes (1F31DK130278-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10312642. Licensed CC0.

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