# Defining the Impact of Immunodeficiency Virus Infection on Mycobacteria-Specific, Unconventional CD8+ T cells

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $254,901

## Abstract

PROJECT SUMMARY/ABSTRACT
Approximately one-third of the world’s population is infected with Mycobacterium tuberculosis. These numbers
are compounded by the extraordinary prevalence of human immunodeficiency virus. Given the emergence of
multidrug-resistant TB, there is an urgent need for new TB vaccines that can either prevent or therapeutically
treat Mtb. Further, provided the overlap in Mtb and HIV prevalence, we must understand how HIV dismantles
immunity to TB. CD8+ T cells are an important component of TB control, but vaccines targeting conventional
CD8+ T cells face hurdles that may require tailored vaccines. Here, we propose to study two novel populations
of unconventional Mtb-specific CD8+ T cells, mucosal-associated invariant T cells (MAITs) and MHC-E restricted
CD8+ T cells (MERTs) in NHPs. We will use a multifaceted approach to establish these populations as new
universal TB vaccine targets in a physiologically relevant animal model of HIV/TB co-infection. MAITs are
enriched in the lung, have immediate adaptive and innate-like immune function upon thymic egress, and contain
early Mtb replication. MAITs recognize vitamin B metabolites in the context of MHC-related protein 1 (MR1).
MR1 is a highly conserved, MHC-Ib molecule that acts as a sensor of bacterial infection. Similarly, MHC-E is a
highly conserved, non-classical, MHC class Ib molecule. In healthy cells, MHC-E binds the VL9 leader peptide
of MHC class I molecules and presents them on the cell surface, signaling to natural killer cells that antigen
processing and presentation is proceeding normally. However, in the context of certain viral and bacterial
infections, MHC-E can present a surprising array of pathogen-derived peptides to MHC-E restricted CD8+ T cells
(MERTs). The goal of this study is to characterize these two mycobacteria-specific, unconventional T cell
populations and to understand how immunodeficiency virus impacts their function. We have generated exciting
preliminary data demonstrating the existence of MAITs and MERTs in rhesus macaques (RM). RM are an
excellent model for studying novel TB vaccines and the impact of HIV infection. We hypothesize that IV BCG will
drive antigen-specific MAIT and MERT expansion and that SIV will lead to BCG-specific MAIT and MERT
dysfunction. We will define BCG-specific MAIT and MERT TCR usage and function after IV BCG vaccination
and determine the impact of SIV on these cells using flow cytometry and single cell RNAseq (scRNAseq). This
multipronged approach will assess MAITs and MERTs as universal TB vaccine targets and interrogate their
sensitivity to immunodeficiency virus-induced immune destruction.

## Key facts

- **NIH application ID:** 9995417
- **Project number:** 5R21AI147944-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Jonah B. Sacha
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,901
- **Award type:** 5
- **Project period:** 2019-08-14 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995417

## Citation

> US National Institutes of Health, RePORTER application 9995417, Defining the Impact of Immunodeficiency Virus Infection on Mycobacteria-Specific, Unconventional CD8+ T cells (5R21AI147944-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9995417. Licensed CC0.

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